CN102229732B - Method for preparing semi-interpenetrating-network-structure-based pH stimulus response nano hydrogel - Google Patents
Method for preparing semi-interpenetrating-network-structure-based pH stimulus response nano hydrogel Download PDFInfo
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Abstract
The invention relates to a method for preparing a semi-interpenetrating-network-structure-based pH stimulus response nano hydrogel. The method comprises the following steps of: (1) preparing aqueous solution of a polymer, regulating the pH value to be between 3 and 7, adding a monomer and a cross-linker into the aqueous solution of the polymer, introducing nitrogen, stirring the solution, heating the solution to the temperature of between 60 and 80 DEG C, and maintaining the temperature for 20 to 40 minutes to obtain aqueous solution of reactants; and (2) preparing aqueous solution of an initiator, adding the aqueous solution of the initiator into the aqueous solution of the reactants, heating the solution to the temperature of between 60 and 80 DEG C, introducing nitrogen, reacting for 4 to 6 hours, cooling the product to room temperature after the reaction is finished, and performing centrifugal separation on the product to obtain the pH stimulus response nano hydrogel. The method is simple, low in cost and suitable for batch production; and the water dispersion of the nano hydrogel prepared by the method has high stability and good application prospect.
Description
Technical field
The invention belongs to the preparation field of nano-hydrogel, particularly a kind of preparation method of the pH stimulating responsive nano-hydrogel based on half interpenetrating network structure.
Background technology
Nano-hydrogel is the polyalcohol hydrogel particle of a kind of particle diameter in the 10nm-1000nm scope, have that size is little, the characteristics such as specific surface area is large, fast response time, encapsulation rate are good, good stability, injectable, thereby separate in drug conveying, biological substance and chemical substance, the fields such as makeup, oil production have a good application prospect.PH stimulating responsive nano-hydrogel is a kind of intelligent nano hydrogel, its can response environment pH value variation and the noticeable change of the physical and chemical performances such as volume, water content, refractive index, rate of permeation, hydrophilic-hydrophobic occurs.In the human body in different sites even the cell not the pH value of device born of the same parents all be very different.In digestion, stomach pH value is about 1～2, and the pH of intestines section value reaches about 7～8.The pH value of the many lesions positions of human body such as tumour, inflammation tissue etc. is lower than the pH value at normal position.Therefore utilize the variation of human body different sites or lesions position pH value, domestic and international investigator is studying always pH stimulating responsive nano-hydrogel is being used for the targeted drug delivery carrier for many years, reaches the raising curative effect, reduces the purpose of side effect.Drug conveying requires the pH value variation range of generation pH stimulating responsive little with pH stimulating responsive nano-hydrogel, and the amplitude that volume change occurs is large, and namely the pH stimulating responsive is strong.
Usually contain ionogen in the macromolecular skeleton chain of pH stimulating responsive nano-hydrogel, such as hydroxy-acid group or amine groups etc.Owing to these groups can change the ionization that produces in various degree along with dispersion medium pH value, the osmotic pressure of nano-hydrogel inside is changed, thereby cause that discontinuous swelling volume changes, and demonstrates the pH stimulating responsive.For the pH stimulating responsive nano-hydrogel with the slightly acidic group, if dispersion medium pH value is greater than the ionization equilibrium constant (pK of slightly acidic group
a), then the ionization of the slightly acidic group on the hydrogel molecular chain side chain forms charged negatively charged ion, thereby at the larger osmotic pressure of the inner generation of hydrogel, makes swelling behavior.Same reason, with the nano-hydrogel of weakly alkaline group then in water medium pH value less than its ionization equilibrium constant pK
bThe time produce swelling.
Past, the synthetic the most frequently used method of pH stimulating responsive nano-hydrogel was the conversed phase micro emulsion copolymerization method.Conversed phase micro emulsion copolymerization is at first monomer, dispersion medium, emulsifying agent and various auxiliarys etc. to be mixed with microemulsion, takes the appropriate means trigger monomer polymerizations such as thermal initiation or radiation initiation again.(the Bouillot P such as Bouillot P, Vincent B.Colloid and Polymer Science, 2000,278 (1): 74-79.) at first adopt the conversed phase micro emulsion copolymerization method to synthesize polyacrylamide, then add vinylformic acid, linking agent, initiator and carry out the second step building-up reactions and make the pH stimulating responsive nano-hydrogel that the poly propenoic acid acrylamide forms.Need after reaction is finished to remove organic solvent by distillation under vacuum, obtain nano-hydrogel with methyl alcohol as precipitation agent again, carry out purifying by dialysis at last.Although the big or small homogeneous of the Hydrogel Nanoparticles that obtains son, dispersion stabilization is good and have the pH stimulating responsive, owing to doing reaction medium with organic solvent, so preparation technology does not have environment friendly.Use in addition a large amount of emulsifying agents and assistant for emulsifying agent in the reaction system, bring pollution for pH stimulating responsive nano-hydrogel, be unfavorable for for drug conveying.
It is that its pH responsive is the Key Performance Indicator of this class intelligent nano hydrogel that pH stimulating responsive nano-hydrogel response environment pH value changes the big or small machine that volume change occurs.The pH responsive is higher, its as pharmaceutical carrier more favourable aspect the drug controllable release.There is the not high problem of pH responsive mostly in the past pH stimulating responsive nano-hydrogel of research, such as (Saunders BR, Vincent B.Adv Colloid Interface Sci 1999 such as Saunders; 80:1.) synthesized poly-(methyl methacrylate-co-methacrylic acid) nano-hydrogel, under different pH values, survey its change of size, found that its volume change degree is less than 10 times.The people such as Tan have studied swelling behavior (the Tan BH of the pH stimulating responsive nano-hydrogel that is formed by methacrylic acid, ethyl propenoate and diallyphthalate base ester, Tam KC, Lam YC, Tan CB.Adv Colloid Interface Sci2005; 113:111.), find the variation along with environment pH value, even the dissociation degree of hydroxy-acid group changes to 1, about 90 times of its volume growth from 0 in the nano-hydrogel.On the whole, the pH stimulating responsive of the pH stimulating responsive nano-hydrogel of past research is more weak, and the scope of volume change is generally in 100 times.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of the pH stimulating responsive nano-hydrogel based on half interpenetrating network structure, and the method technique is simple, and cost is low, is suitable for batch production; The nano-hydrogel aqueous dispersions stability of preparation is high, has a good application prospect.
The preparation method of a kind of pH stimulating responsive nano-hydrogel based on half interpenetrating network structure of the present invention comprises:
(1) linear polymer being dissolved in deionized water, to be mixed with mass percent concentration be 0.1～20% aqueous solutions of polymers, regulate pH value to 3～7, then in aqueous solutions of polymers, add monomer and linking agent, wherein, the mass percent concentration of monomer is 0.1～20%, and dosage of crosslinking agent is 0.02～5% of monomer mass; Pass into nitrogen and stir, be warming up to 60～80 ℃ and kept 20～40 minutes, get reactant aqueous solution;
(2) at room temperature preparing mass percent concentration is 1～10% initiator solution, join in above-mentioned reactant aqueous solution by 0.1～1% of monomer mass in the step (1) initiator solution and be heated to 60～80 ℃, pass into nitrogen, reacted 4～6 hours, be cooled to room temperature after reaction finishes, product centrifugation (remove unreacted monomer, linking agent, initiator and do not advance linear polymer in people's nano-hydrogel) is namely got pH stimulating responsive nano-hydrogel.
Linear polymer in the described step (1) is a kind of in polyacrylic acid, polyacrylic acid sodium salt or ammonium salt, polymethyl acrylic acid, sodium polymethacrylate salt or the ammonium salt.
Adjusting pH value in the described step (1) adopts the HCl aqueous solution of 0.1M or the NaOH aqueous solution of 0.1M.
Monomer in the described step (1) is NIPA, N tert butyl acrylamide, N-n-propyl acrylamide, N-isopropyl methyl acrylamide or N-n-propyl Methacrylamide.
Linking agent in the described step (1) is methylene-bisacrylamide or four condensed ethandiol double methacrylates.
Stirring velocity in the described step (1) is 100～400 rev/mins.
Initiator in the described step (2) is Potassium Persulphate or ammonium persulphate.
The nano-hydrogel of the present invention's preparation can be regulated the particle diameter of nano-hydrogel by change reaction medium pH value, the consumption of linear polymer, the consumption of linking agent.The nano-hydrogel of preparation has superpower pH stimulating responsive, and when the pH of water medium value was increased to 6.0 from 4.0, its volume change can reach more than 100 times, and the nano-hydrogel aqueous dispersions becomes colorless transparent from oyster white in appearance.
Beneficial effect
(1) technique of the present invention is simple, and cost is low, is suitable for batch production, adopts in the preparation process and uses water as reaction medium, produces without poisonous and hazardous by product, and is environmentally friendly;
(2) the nano-hydrogel aqueous dispersions of the present invention preparation stability is high, and nano-hydrogel is half interpenetrating network structure, at room temperature deposits the half a year thing and produces without any flocculation or throw out, has a good application prospect.
Description of drawings
Fig. 1 is the D of the pH value stimulating responsive nano-hydrogel of embodiment 1 preparation
HThe relation curve of～pH.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after the content of having read the present invention's instruction, these equivalent form of values fall within the application's appended claims limited range equally.
Embodiment 1
The 0.75g polyacrylic acid is dissolved in the 90ml deionized water, after the stirring and dissolving, with 0.1M aqueous hydrochloric acid furnishing pH=3 ± 0.2, again 0.5g N-isopropylacrylamide, 0.02g methylene-bisacrylamide is joined in the polyacrylic acid aqueous solution.Pass into nitrogen, stirring velocity is 300 rev/mins, is warming up to gradually 75 ℃, and balance is stand-by after 30 minutes.
The 0.01g ammonium persulfate initiator is dissolved in the 3ml deionized water, joins again in the above-mentioned reactant aqueous solution, continue logical nitrogen, be controlled under above-mentioned stirring velocity and the temperature and reacted 5 hours.Reaction is cooled to room temperature after finishing, and products therefrom is milky nano-hydrogel aqueous dispersions.
Gained nano-hydrogel aqueous dispersions is passed through the high speed centrifugation that repeats for 3 times, the purifying process of ultra-sonic dispersion, remove unreacted monomer, linking agent or do not advance the linear polymer of people in the nano-hydrogel, obtain the nano-hydrogel aqueous dispersions of half interpenetrating network structure.
Be under 3.0～7.0 the condition in the pH value, adopt the particle diameter of dynamic laser light scattering apparatus test nano-hydrogel, the result is for being that the volume of nano-hydrogel is from 140 in 4.0 to 6.0 the scope in the pH value
3Nm
3Change to 900
3Nm
3
Embodiment 2
The 0.75g polyacrylic acid is dissolved in the 90ml deionized water, and after the stirring and dissolving, the aqueous sodium hydroxide solution furnishing pH=7 of usefulness 0.1M ± 0.2 joins 0.5g N-isopropylacrylamide, 0.02g methylene-bisacrylamide in the polyacrylic acid aqueous solution again.Pass into nitrogen, stirring velocity is 300 rev/mins, is warming up to gradually 75 ℃, and balance is stand-by after 30 minutes.
The 0.01g ammonium persulfate initiator is dissolved in the 3ml deionized water, joins again in the above-mentioned reactant aqueous solution, continue logical nitrogen, be controlled under above-mentioned stirring velocity and the temperature and reacted 5 hours.Reaction is cooled to room temperature after finishing, and products therefrom is milky nano-hydrogel aqueous dispersions.
Gained nano-hydrogel aqueous dispersions is passed through the high speed centrifugation that repeats for 3 times, the purifying process of ultra-sonic dispersion, remove unreacted monomer, linking agent or do not advance the linear polymer of people in the nano-hydrogel, obtain the nano-hydrogel aqueous dispersions of half interpenetrating network structure.
Be under 3.0～7.0 the condition in the pH value, adopt the particle diameter of dynamic laser light scattering apparatus test nano-hydrogel, the result is for being that the volume of nano-hydrogel is from 140 in 4.0 to 6.0 the scope in the pH value
3Nm
3Change to 550
3Nm
3
The 2g polyacrylic acid is dissolved in the 100ml deionized water, after the stirring and dissolving, with aqueous hydrochloric acid or aqueous sodium hydroxide solution furnishing pH=3 ± 0.2, again 2g N-isopropylacrylamide, 0.1g methylene-bisacrylamide is joined in the polyacrylic acid aqueous solution.Pass into nitrogen, stirring velocity is 100 rev/mins, is warming up to gradually 80 ℃, and balance is stand-by after 40 minutes.
The 0.02g ammonium persulfate initiator is dissolved in the 2ml deionized water, joins again in the above-mentioned reactant aqueous solution, continue logical nitrogen, be controlled under above-mentioned stirring velocity and the temperature and reacted 6 hours.Reaction is cooled to room temperature after finishing, and products therefrom is milky nano-hydrogel aqueous dispersions.
Gained nano-hydrogel aqueous dispersions is passed through the high speed centrifugation that repeats for 3 times, the purifying process of ultra-sonic dispersion, remove unreacted monomer, linking agent or do not advance the linear polymer of people in the nano-hydrogel, obtain the nano-hydrogel aqueous dispersions of half interpenetrating network structure.
Be under 3.0～7.0 the condition in the pH value, adopt the particle diameter of dynamic laser light scattering apparatus test nano-hydrogel, the result is for being that the volume of nano-hydrogel is from 170 in 4.0 to 6.0 the scope in the pH value
3Nm
3Change to 950
3Nm
3
Embodiment 4
The 0.2g polyacrylic acid is dissolved in the 100ml deionized water, after the stirring and dissolving, with aqueous hydrochloric acid or aqueous sodium hydroxide solution furnishing pH=3 ± 0.2, again 0.2g N-isopropylacrylamide, 0.002g methylene-bisacrylamide is joined in the polyacrylic acid aqueous solution.Pass into nitrogen, stirring velocity is 400 rev/mins, is warming up to gradually 60 ℃, and balance is stand-by after 20 minutes.
The 0.001g ammonium persulfate initiator is dissolved in the 2ml deionized water, joins again in the above-mentioned reactant aqueous solution, continue logical nitrogen, be controlled under above-mentioned stirring velocity and the temperature and reacted 4 hours.Reaction is cooled to room temperature after finishing, and products therefrom is milky nano-hydrogel aqueous dispersions.
Gained nano-hydrogel aqueous dispersions is passed through the high speed centrifugation that repeats for 3 times, the purifying process of ultra-sonic dispersion, remove unreacted monomer, linking agent or do not advance the linear polymer of people in the nano-hydrogel, obtain the nano-hydrogel aqueous dispersions of half interpenetrating network structure.
Be under 3.0～7.0 the condition in the pH value, adopt the particle diameter of dynamic laser light scattering apparatus test nano-hydrogel, the result is for being that the volume of nano-hydrogel is from 140 in 4.0 to 6.0 the scope in the pH value
3Nm
3Change to 940
3Nm
3
Claims (5)
1. preparation method based on the pH stimulating responsive nano-hydrogel of half interpenetrating network structure comprises:
(1) linear polymer being dissolved in deionized water, to be mixed with mass percent concentration be 0.1～20% aqueous solutions of polymers, regulate pH value to 3～7, then in aqueous solutions of polymers, add monomer and linking agent, wherein, the mass percent concentration of monomer is 0.1～20%, and dosage of crosslinking agent is 0.02～5% of monomer mass; Pass into nitrogen and stir, be warming up to 60～80 ℃ and kept 20～40 minutes, get reactant aqueous solution; Wherein, linear polymer is a kind of in polyacrylic acid, polyacrylic acid sodium salt or ammonium salt, polymethyl acrylic acid, sodium polymethacrylate salt or the ammonium salt; Monomer is NIPA, N tert butyl acrylamide, N-n-propyl acrylamide, N-isopropyl methyl acrylamide or N-n-propyl Methacrylamide;
(2) at room temperature preparing mass percent concentration is 1～10% initiator solution, join in above-mentioned reactant aqueous solution by 0.1～1% of monomer mass in the step (1) initiator solution and be heated to 60～80 ℃, pass into nitrogen, reacted 4～6 hours, reaction is cooled to room temperature after finishing, and the product centrifugation is namely got pH stimulating responsive nano-hydrogel.
2. the preparation method of a kind of pH stimulating responsive nano-hydrogel based on half interpenetrating network structure according to claim 1, it is characterized in that: the adjusting pH value in the described step (1) adopts the HCl aqueous solution of 0.1M or the NaOH aqueous solution of 0.1M.
3. the preparation method of a kind of pH stimulating responsive nano-hydrogel based on half interpenetrating network structure according to claim 1, it is characterized in that: the linking agent in the described step (1) is methylene-bisacrylamide or four condensed ethandiol double methacrylates.
4. the preparation method of a kind of pH stimulating responsive nano-hydrogel based on half interpenetrating network structure according to claim 1, it is characterized in that: the stirring velocity in the described step (1) is 100～400 rev/mins.
5. the preparation method of a kind of pH stimulating responsive nano-hydrogel based on half interpenetrating network structure according to claim 1, it is characterized in that: the initiator in the described step (2) is Potassium Persulphate or ammonium persulphate.
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