CN101845120B - Method for synthesizing temperature-sensitive and biodegradable in situ gel - Google Patents
Method for synthesizing temperature-sensitive and biodegradable in situ gel Download PDFInfo
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- CN101845120B CN101845120B CN2010101377596A CN201010137759A CN101845120B CN 101845120 B CN101845120 B CN 101845120B CN 2010101377596 A CN2010101377596 A CN 2010101377596A CN 201010137759 A CN201010137759 A CN 201010137759A CN 101845120 B CN101845120 B CN 101845120B
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- 238000011065 in-situ storage Methods 0.000 title claims abstract description 10
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- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 claims abstract description 25
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- 239000001301 oxygen Substances 0.000 claims abstract description 12
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- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 claims abstract description 10
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims abstract description 5
- 235000010262 sodium metabisulphite Nutrition 0.000 claims abstract description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 97
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 88
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 34
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- 229920000428 triblock copolymer Polymers 0.000 claims description 25
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- 239000000178 monomer Substances 0.000 claims description 23
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- 238000001035 drying Methods 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
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- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000006185 dispersion Substances 0.000 claims description 12
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- 241000237502 Ostreidae Species 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 238000004132 cross linking Methods 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 11
- 239000000839 emulsion Substances 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 11
- 230000006698 induction Effects 0.000 claims description 11
- 235000020636 oyster Nutrition 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 11
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-UHFFFAOYSA-N 0.000 claims description 11
- 238000007789 sealing Methods 0.000 claims description 11
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims description 11
- 238000005303 weighing Methods 0.000 claims description 11
- 238000010189 synthetic method Methods 0.000 claims description 8
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 5
- 239000004160 Ammonium persulphate Substances 0.000 claims description 4
- 235000019395 ammonium persulphate Nutrition 0.000 claims description 4
- PYGSKMBEVAICCR-UHFFFAOYSA-N hexa-1,5-diene Chemical group C=CCCC=C PYGSKMBEVAICCR-UHFFFAOYSA-N 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract description 2
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 abstract 2
- 229910001870 ammonium persulfate Inorganic materials 0.000 abstract 1
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- 230000035945 sensitivity Effects 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 40
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
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- PKZCRWFNSBIBEW-UHFFFAOYSA-N 2-n,2-n,2-trimethylpropane-1,2-diamine Chemical compound CN(C)C(C)(C)CN PKZCRWFNSBIBEW-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
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- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
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- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 1
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Abstract
本发明公开了一种温敏和生物可降解性原位凝胶的合成方法，该原位凝胶由N-异丙基丙烯酰胺、引发剂、可生物降解交联剂在二次蒸馏水中无氧的条件下加热聚合得到；PLA-PEG-PLA三嵌段共聚物由丙交酯与PEG本体聚合而得，PEG分子量为4000或6000，LA/PEG摩尔比为3∶1、5∶1或8∶1，PLEL与NIPAM质量比为(1-10)∶(25-75)；引发剂为：过硫酸铵/焦亚硫酸钠、偶氮二异丁腈、N，N，N′，N′-四甲基乙二胺或硝酸铈铵，依NIPAM计，引发剂为其质量的0.6％-0.8％。该合成方法得到的原位凝胶具有温敏性、对生物体无毒性、良好的生物相容性和可降解性，可应用于药物释放体系、酶的固定、蛋白质分离和纯化等生物医学领域。
The invention discloses a method for synthesizing thermosensitive and biodegradable in-situ gel. The in-situ gel is composed of N-isopropylacrylamide, initiator and biodegradable cross-linking agent in twice distilled water without oxygen. The PLA-PEG-PLA tri-block copolymer is obtained by bulk polymerization of lactide and PEG, the molecular weight of PEG is 4000 or 6000, and the molar ratio of LA/PEG is 3:1, 5:1 or 8 : 1, the mass ratio of PLEL to NIPAM is (1-10): (25-75); the initiator is: ammonium persulfate/sodium pyrosulfite, azobisisobutyronitrile, N, N, N', N'-tetra Methylethylenediamine or ceric ammonium nitrate, according to NIPAM, the initiator is 0.6%-0.8% of its mass. The in situ gel obtained by this synthesis method has temperature sensitivity, non-toxicity to organisms, good biocompatibility and degradability, and can be applied in biomedical fields such as drug release system, enzyme immobilization, protein separation and purification, etc. .
Description
Technical field
The present invention relates to chemical synthesis process, be specifically related to a kind of synthetic method of temperature sensitive and biodegradable in situ gel.
Background material
Situ-gel is a kind of novel medicament transfer system, sol-gel (so-gel) takes place under certain environmental stimulus after the administration change, and forms the transparent solid and the gel of semi-solid at medicine-feeding part.In useful for drug delivery, situ-gel has shown great potential in cell microcapsule technology and the tissue repair field, has obtained in recent years deeply and extensive studies.Wherein, the temperature sensing in situ gel rubber system with the factor of temperature as regulation and control so-gel transformation, has been avoided the use of organic solvent and other chemical substance because of only, has become the research focus at present.In the reported temperature sensitive polymer system, it is the most extensive that poly N-isopropyl acrylamide (PNIPAM) is studied, its lowest critical solution temperature (LCST) is about 32 ℃, near the Human Physiology temperature, and can therefore be widely used in fields such as drug release, organizational project, bioseparation easily by changing with other monomer copolymerization.Yet PNIPAM does not possess biological degradability, lacks excellent biological compatibility, has limited its application on biomedicine.Make it to have concurrently temperature sensitive property, biocompatibility and degradability if in the PNIPAM polymkeric substance, introduce degradable components, and be used for biomedical sector and will demonstrate more great vitality.The polyoxyethylene glycol (PEG) and poly(lactic acid) (PLA) triblock copolymer that have with acrylate ended are a kind of degradable crosslinkers, wherein PLA has obtained the approval of FDA (FDA) as a kind of important Biodegradable polymer material, and PEG can be applicable to the polymkeric substance of human body as a kind of wetting ability and the approval that obtained FDA, have good biocompatibility and blood compatibility, and wetting ability and flexibility preferably, can be dissolved in the tissue juice in vivo, can be excreted rapidly by body and not produce any toxic side effects, therefore the multipolymer of PLA and PEG is widely used for medical aspect by people as the degradable biological material.Therefore, synthetic and research has temperature sensitive and situ-gel biodegradability, and it is used for medicine sustained release field important practical sense.
Summary of the invention
The objective of the invention is to: the synthetic method that a kind of temperature sensitive and biodegradable in situ gel is provided, this synthetic method obtains situ-gel by N-N-isopropylacrylamide and the biodegradable linking agent polymerization of the end capped PLA-PEG-PLA of diallyl (PLEL), this situ-gel not only has temperature sensitive property, and have organism nontoxicity, excellent biological compatibility and biodegradability, can be applicable to biomedical sectors such as fixing, the protein separation of drug delivery system, enzyme and purifying.
Technical solution of the present invention is: this situ-gel by N-N-isopropylacrylamide, initiator, the biodegradable linking agent of the end capped PLA-PEG-PLA of diallyl in redistilled water, heated polymerizable obtains under the condition of anaerobic; The PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 4000 or 6000, the LA/PEG mol ratio is 3: 1,5: 1 or 8: 1, and according to the PLEL meter, PLEL and NIPAM mass ratio are (1-10): (25-75); Initiator is: ammonium persulphate/Sodium Pyrosulfite, Diisopropyl azodicarboxylate, N,N,N or ceric ammonium nitrate, according to the NIPAM meter, initiator is the 0.6%-0.8% of its quality.
Concrete steps of the present invention are as follows:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization respectively
nBe 4000 or 6000, the LA/PEG mol ratio is 3: 1,5: 1 or 8: 1, and the polymerization crude product is with being in excess in its weight 1-3 methylene dichloride dissolving doubly, again with being in excess in methylene dichloride weight 3-4 petroleum ether precipitation purifying doubly, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with being in excess in its weight 1-3 methylene dichloride dissolving back doubly, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, the TEA/PLA-PEG-PLA mol ratio is 3: 1, the AcCl/PLA-PEG-PLA mol ratio is 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with being in excess in methylene dichloride weight 3-4 petroleum ether precipitation doubly;
3, take by weighing 0.5-15g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 20-200mg PLEL, stir, logical nitrogen 30-60min removes the oxygen in the system;
4, count according to NIPAM, the initiator of its quality 0.6%-0.8% is dissolved in the 4ml distilled water forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min, to install sealing and place water bath with thermostatic control, and stir, temperature is controlled at 50-80 ℃ of crosslinking polymerization, reaction 7h, whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
The present invention has the following advantages: 1, synthetic PNIPAM situ-gel had both had temperature sensitive property, overcome simultaneously the shortcoming of conventional P NIPAM gel non-degradable and biocompatibility difference again, and this hydrogel original position formation in vivo, need not to be injected in the body under the operating situation, avoid the height in the surgical procedures traumatic, healing acceleration, reduce patient's misery, especially when being used to repair the organizing of complicated shape, situ-gel has adaptivity, but body temperature solidifies, and this is that the traditional water gel is incomparable.
2, the ratio of molecular weight by changing polyoxyethylene glycol and LA/PEG is regulated the gelling temperature of this gel, make it under storage condition is free-pouring liquid, after entering human body, injection can be filled in tissue space, take place rapidly in vivo to change mutually, reach topical or delay the purpose of drug release.
3, the situ-gel synthetic method is safe and reliable, and is simple to operate, and material is easy to get, the reaction conditions gentleness, and reaction medium is a water, aftertreatment is easy.
Description of drawings
Fig. 1 is the phasor of the gel dispersion that makes of different linking agent PLEL consumptions.
Embodiment
Further specify technical solution of the present invention below in conjunction with specific embodiment, these embodiment can not be interpreted as it is restriction to technical scheme.
Embodiment 1: according to the following steps synthesized gel rubber:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 4000, the LA/PEG mol ratio is 3: 1, and the polymerization crude product is with the methylene dichloride dissolving that is in excess in 1 times of its weight, again with the petroleum ether precipitation purifying that is in excess in 3 times of methylene dichloride weight, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with the methylene dichloride dissolving back that is in excess in 1 times of its weight, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, the TEA/PLA-PEG-PLA mol ratio is 3: 1, the AcCl/PLA-PEG-PLA mol ratio is 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with the petroleum ether precipitation that is in excess in 3 times of methylene dichloride weight;
3, take by weighing 0.5g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 20mgPLEL, stir, logical nitrogen 30min removes the oxygen in the system;
4, count according to NIPAM, ammonium persulphate/the Sodium Pyrosulfite of its quality 0.6% is dissolved in respectively in the 4ml distilled water forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min, to install sealing and place water bath with thermostatic control, and stir, temperature is controlled at 50 ℃ of crosslinking polymerizations, reaction 7h, whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
Embodiment 2: according to the following steps synthesized gel rubber:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 6000, the LA/PEG mol ratio is 5: 1, and the polymerization crude product is with the methylene dichloride dissolving that is in excess in 2 times of its weight, again with the petroleum ether precipitation purifying that is in excess in 3.5 times of methylene dichloride weight, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with the methylene dichloride dissolving back that is in excess in 2 times of its weight, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, TEA/PLA-PEG-PLA mol ratio 3: 1, AcCl/PLA-PEG-PLA mol ratio 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with the petroleum ether precipitation that is in excess in 3.5 times of methylene dichloride weight;
3, take by weighing 1.0g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 20mgPLEL, stir, logical nitrogen 45min removes the oxygen in the system;
4, count according to NIPAM, the Diisopropyl azodicarboxylate of its quality 0.7% is dissolved in the 4ml distilled water forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min, to install sealing and place water bath with thermostatic control, and stir, temperature is controlled at 65 ℃ of crosslinking polymerizations, reaction 7h, whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
Embodiment 3: according to the following steps synthesized gel rubber:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 4000, the LA/PEG mol ratio is 8: 1, and the polymerization crude product is with the methylene dichloride dissolving that is in excess in 3 times of its weight, again with the petroleum ether precipitation purifying that is in excess in 4 times of methylene dichloride weight, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with the methylene dichloride dissolving back that is in excess in 3 times of its weight, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, TEA/PLA-PEG-PLA mol ratio 3: 1, AcCl/PLA-PEG-PLA mol ratio 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with the petroleum ether precipitation that is in excess in 4 times of methylene dichloride weight;
3, take by weighing 1.5g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 20mgPLEL, stir, logical nitrogen 60min removes the oxygen in the system;
4, count according to NIPAM, with the N of its quality 0.8%, N, N ', N '-Tetramethyl Ethylene Diamine is dissolved in the 4ml distilled water and forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min will install sealing and place water bath with thermostatic control, stir, temperature is controlled at 80 ℃ of crosslinking polymerizations, reaction 7h, and whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
Embodiment 4: according to the following steps synthesized gel rubber:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 6000, the LA/PEG mol ratio is 3: 1, and the polymerization crude product is with the methylene dichloride dissolving that is in excess in 1 times of its weight, again with the petroleum ether precipitation purifying that is in excess in 3 times of methylene dichloride weight, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with the methylene dichloride dissolving back that is in excess in 1 times of its weight, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, TEA/PLA-PEG-PLA mol ratio 3: 1, AcCl/PLA-PEG-PLA mol ratio 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with the petroleum ether precipitation that is in excess in 3 times of methylene dichloride weight;
3, take by weighing 2.5g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 100mg PLEL, stir, logical nitrogen 30min removes the oxygen in the system;
4, count according to NIPAM, the ceric ammonium nitrate of its quality 0.6% is dissolved in the 4ml distilled water forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min, to install sealing and place water bath with thermostatic control, and stir, temperature is controlled at 50 ℃ of crosslinking polymerizations, reaction 7h, whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
Embodiment 5: according to the following steps synthesized gel rubber:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 4000, the LA/PEG mol ratio is 5: 1, and the polymerization crude product is with the methylene dichloride dissolving that is in excess in 2 times of its weight, again with the petroleum ether precipitation purifying that is in excess in 3.5 times of methylene dichloride weight, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with the methylene dichloride dissolving back that is in excess in 2 times of its weight, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, TEA/PLA-PEG-PLA mol ratio 3: 1, AcCl/PLA-PEG-PLA mol ratio 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with the petroleum ether precipitation that is in excess in 3.5 times of methylene dichloride weight;
3, take by weighing 5.0g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 100mg PLEL, stir, logical nitrogen 45min removes the oxygen in the system;
4, count according to NIPAM, the Diisopropyl azodicarboxylate of its quality 0.7% is dissolved in the 4ml distilled water forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min, to install sealing and place water bath with thermostatic control, and stir, temperature is controlled at 65 ℃ of crosslinking polymerizations, reaction 7h, whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
Embodiment 6: according to the following steps synthesized gel rubber:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 6000, the LA/PEG mol ratio is 8: 1, and the polymerization crude product is with the methylene dichloride dissolving that is in excess in 3 times of its weight, again with the petroleum ether precipitation purifying that is in excess in 4 times of methylene dichloride weight, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with the methylene dichloride dissolving back that is in excess in 3 times of its weight, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, TEA/PLA-PEG-PLA mol ratio 3: 1, AcCl/PLA-PEG-PLA mol ratio 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with the petroleum ether precipitation that is in excess in 4 times of methylene dichloride weight;
3, take by weighing 7.5g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 100mg PLEL, stir, logical nitrogen 60min removes the oxygen in the system;
4, count according to NIPAM, ammonium persulphate/the Sodium Pyrosulfite of its quality 0.8% is dissolved in respectively in the 4ml distilled water forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min, to install sealing and place water bath with thermostatic control, and stir, temperature is controlled at 80 ℃ of crosslinking polymerizations, reaction 7h, whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
Embodiment 7: according to the following steps synthesized gel rubber:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 4000, the LA/PEG mol ratio is 3: 1, and the polymerization crude product is with the methylene dichloride dissolving that is in excess in 1 times of its weight, again with the petroleum ether precipitation purifying that is in excess in 3 times of methylene dichloride weight, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with the methylene dichloride dissolving back that is in excess in 1 times of its weight, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, TEA/PLA-PEG-PLA mol ratio 3: 1, AcCl/PLA-PEG-PLA mol ratio 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with the petroleum ether precipitation that is in excess in 3 times of methylene dichloride weight;
3, take by weighing 5.0g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 200mg PLEL, stir, logical nitrogen 30min removes the oxygen in the system;
4, count according to NIPAM, with the N of its quality 0.6%, N, N ', N '-Tetramethyl Ethylene Diamine is dissolved in the 4ml distilled water and forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min will install sealing and place water bath with thermostatic control, stir, temperature is controlled at 50 ℃ of crosslinking polymerizations, reaction 7h, and whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
Embodiment 8: according to the following steps synthesized gel rubber:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 6000, the LA/PEG mol ratio is 5: 1, and the polymerization crude product is with the methylene dichloride dissolving that is in excess in 2 times of its weight, again with the petroleum ether precipitation purifying that is in excess in 3.5 times of methylene dichloride weight, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with the methylene dichloride dissolving back that is in excess in 2 times of its weight, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, TEA/PLA-PEG-PLA mol ratio 3: 1, AcCl/PLA-PEG-PLA mol ratio 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with the petroleum ether precipitation that is in excess in 3.5 times of methylene dichloride weight;
3, take by weighing 10.0g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 200mg PLEL, stir, logical nitrogen 45min removes the oxygen in the system;
4, count according to NIPAM, the Diisopropyl azodicarboxylate of its quality 0.7% is dissolved in the 4ml distilled water forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min, to install sealing and place water bath with thermostatic control, and stir, temperature is controlled at 65 ℃ of crosslinking polymerizations, reaction 7h, whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
Embodiment 9: according to the following steps synthesized gel rubber:
1, the PLA-PEG-PLA triblock copolymer gets PEG molecular weight M by rac-Lactide (LA) with the PEG mass polymerization
nBe 6000, the LA/PEG mol ratio is 8: 1, and the polymerization crude product is with the methylene dichloride dissolving that is in excess in 3 times of its weight, again with the petroleum ether precipitation purifying that is in excess in 4 times of methylene dichloride weight, purifying after product and 40 ℃ of drying under reduced pressure;
2, above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with the methylene dichloride dissolving back that is in excess in 3 times of its weight, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine (TEA) and acrylate chloride (AcCl) then, TEA/PLA-PEG-PLA mol ratio 3: 1, AcCl/PLA-PEG-PLA mol ratio 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose (PLEL) with the petroleum ether precipitation that is in excess in 4 times of methylene dichloride weight;
3, take by weighing 15.0g N-N-isopropylacrylamide (NIPAM) and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 200mg PLEL, stir, logical nitrogen 60min removes the oxygen in the system;
4, count according to NIPAM, the ceric ammonium nitrate of its quality 0.8% is dissolved in the 4ml distilled water forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min, to install sealing and place water bath with thermostatic control, and stir, temperature is controlled at 80 ℃ of crosslinking polymerizations, reaction 7h, whole solution is by the colourless oyster white that slowly becomes;
5, after reaction finished, above-mentioned emulsion was put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid to remove unreacted monomer, linking agent.
Claims (2)
1. the synthetic method of a temperature sensitive and biodegradable in situ gel is characterized in that: this situ-gel by N-N-isopropylacrylamide NIPAM, initiator, the biodegradable linking agent PLEL of the end capped PLA-PEG-PLA of diallyl in redistilled water, heated polymerizable obtains under the condition of anaerobic; The PLA-PEG-PLA triblock copolymer is by rac-Lactide LA and PEG mass polymerization and get PEG molecular weight M
nBe 4000 or 6000, the LA/PEG mol ratio is 3: 1,5: 1 or 8: 1, and according to the PLEL meter, PLEL and NIPAM mass ratio are (1-10): (25-75); Initiator is: ammonium persulphate/Sodium Pyrosulfite, Diisopropyl azodicarboxylate, N,N,N or ceric ammonium nitrate, according to the NIPAM meter, initiator is the 0.6%-0.8% of its quality.
2. the synthetic method of a kind of temperature sensitive and biodegradable in situ gel according to claim 1 is characterized in that the concrete steps of synthetic method are as follows:
(1), the PLA-PEG-PLA triblock copolymer is respectively by rac-Lactide LA and PEG mass polymerization and get PEG molecular weight M
nBe 4000 or 6000, the LA/PEG mol ratio is 3: 1,5: 1 or 8: 1, and the polymerization crude product is with being in excess in its weight 1-3 methylene dichloride dissolving doubly, and with being in excess in methylene dichloride weight 3-4 petroleum ether precipitation purifying doubly, the purifying after product is in 40 ℃ of drying under reduced pressure again;
(2), above-mentioned synthetic triblock copolymer is added in the round-bottomed flask with being in excess in its weight 1-3 methylene dichloride dissolving back doubly, flask is placed ice bath, be cooled to 0 ℃, once add triethylamine TEA and acrylate chloride AcCl then, the TEA/PLA-PEG-PLA mol ratio is 3: 1, the AcCl/PLA-PEG-PLA mol ratio is 6: 1, under induction stirring, at 0 ℃ of reaction 6h, at room temperature leave standstill 24h, filter, remove triethylamine hydrochloride, filtrate at last at 40 ℃ of drying under reduced pressure, obtains Biodegradable cross-linked dose of PLEL with being in excess in methylene dichloride weight 3-4 petroleum ether precipitation doubly;
(3), take by weighing 0.5-15g N-N-isopropylacrylamide NIPAM and place three-necked flask, be dissolved in the 30ml distilled water, treat that monomer fully dissolves the back and adds 20-200mg PLEL, stir, logical nitrogen 30-60min removes the oxygen in the system;
(4), count according to NIPAM, the initiator of its quality 0.6%-0.8% is dissolved in the 4ml distilled water forms the aqueous solution, pour into successively in the above-mentioned solution, logical again nitrogen 30min, to install sealing and place water bath with thermostatic control, and stir, temperature is controlled at 50-80 ℃ of crosslinking polymerization, reaction 7h, whole solution is by the colourless oyster white that slowly becomes;
(5), after reaction finishes, above-mentioned emulsion is put into the dialysis tubing dialysis 5d that molecular weight cut-off is 8000-14000, to remove unreacted monomer, linking agent, obtains temperature sensitive at last and biodegradability PNIPAM situ-gel dispersion liquid.
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| US7018655B2 (en) * | 2002-03-18 | 2006-03-28 | Labopharm, Inc. | Amphiphilic diblock, triblock and star-block copolymers and their pharmaceutical compositions |
| WO2007074476A1 (en) * | 2005-12-28 | 2007-07-05 | Dabur Pharma Limited | A biocompatible, non-biodegradable, non-toxic polymer useful for nanoparticle pharmaceutical compositions |
| CN101353398A (en) * | 2008-06-06 | 2009-01-28 | 淮阴师范学院 | A kind of synthetic method of biodegradable thermosensitive gel |
| CN101638485A (en) * | 2009-07-17 | 2010-02-03 | 淮阴师范学院 | Method for synthesizing temperature sensitive degradation PNIPAM/CMCS microgel in nuclear shell structure |
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| US7018655B2 (en) * | 2002-03-18 | 2006-03-28 | Labopharm, Inc. | Amphiphilic diblock, triblock and star-block copolymers and their pharmaceutical compositions |
| WO2007074476A1 (en) * | 2005-12-28 | 2007-07-05 | Dabur Pharma Limited | A biocompatible, non-biodegradable, non-toxic polymer useful for nanoparticle pharmaceutical compositions |
| CN101353398A (en) * | 2008-06-06 | 2009-01-28 | 淮阴师范学院 | A kind of synthetic method of biodegradable thermosensitive gel |
| CN101638485A (en) * | 2009-07-17 | 2010-02-03 | 淮阴师范学院 | Method for synthesizing temperature sensitive degradation PNIPAM/CMCS microgel in nuclear shell structure |
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