CN108530606B - PH-sensitive medical polyurethane urea material and preparation method thereof - Google Patents

PH-sensitive medical polyurethane urea material and preparation method thereof Download PDF

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CN108530606B
CN108530606B CN201810353952.XA CN201810353952A CN108530606B CN 108530606 B CN108530606 B CN 108530606B CN 201810353952 A CN201810353952 A CN 201810353952A CN 108530606 B CN108530606 B CN 108530606B
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polyurethane urea
sensitive medical
polyurethaneurea
lysine diisocyanate
polyurethane
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CN108530606A (en
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侯昭升
刘路路
原栎潼
张鋆
肖铭慧
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Kelai new material technology (Guangzhou) Co.,Ltd.
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Shandong Normal University
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/48—Polyethers
    • C08G18/4833—Polyethers containing oxyethylene units
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/30—Low-molecular-weight compounds
    • C08G18/38—Low-molecular-weight compounds having heteroatoms other than oxygen
    • C08G18/3855—Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur
    • C08G18/3863—Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur containing groups having sulfur atoms between two carbon atoms, the sulfur atoms being directly linked to carbon atoms or other sulfur atoms
    • C08G18/3865—Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur containing groups having sulfur atoms between two carbon atoms, the sulfur atoms being directly linked to carbon atoms or other sulfur atoms containing groups having one sulfur atom between two carbon atoms
    • C08G18/3868—Low-molecular-weight compounds having heteroatoms other than oxygen having sulfur containing groups having sulfur atoms between two carbon atoms, the sulfur atoms being directly linked to carbon atoms or other sulfur atoms containing groups having one sulfur atom between two carbon atoms the sulfur atom belonging to a sulfide group
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/77—Polyisocyanates or polyisothiocyanates having heteroatoms in addition to the isocyanate or isothiocyanate nitrogen and oxygen or sulfur
    • C08G18/78—Nitrogen
    • C08G18/7806—Nitrogen containing -N-C=0 groups
    • C08G18/7812—Nitrogen containing -N-C=0 groups containing amide groups

Abstract

The invention discloses a pH sensitive medical polyurethane urea material and a preparation method thereof, wherein polyurethane urea is prepared by mixing a dihydroxypyridine-terminated compound and double-terminal hydroxyl polyethylene glycol, adding N, N-dimethylformamide for dissolution, then using diisocyanate containing carbamido for chain extension, and purifying to obtain pH sensitive polyurethane urea; the diisocyanate is L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate. The pyridine group of the side chain of the polyurethane urea is Lewis base, and under the acidic condition, the hydrogen bond in the polyurethane urea network is decomposed, so that the discontinuous volume expansion of the material is caused. Removal of H under neutral or alkaline conditions+N on the pyridine ring and NH of the carbamate or the carbamido form a hydrogen bond which is similar to a network structure, so that the molecular chain of the polyurethane urea shrinks and the swelling degree is obviously reduced. Therefore, the swelling degree of the polyurethane urea can be effectively controlled by controlling the change of the pH value of the medium.

Description

PH-sensitive medical polyurethane urea material and preparation method thereof
Technical Field
The invention belongs to the technical field of biological material preparation, particularly relates to the field of intelligent medical high polymer materials, and particularly relates to a preparation method of pH-sensitive medical polyurethane urea.
Background
The intelligent high polymer material can respond to the stimulus of the surrounding environment correspondingly and simultaneously has certain property changes. In the 21 st century, the application of intelligent polyurethane has attracted extensive attention, and this intelligent polyurethane material has found wide application in bioseparation, actuators, controlled drug release and regenerative medicine. The uniqueness of smart polyurethanes is not only that subtle stimuli can cause changes in their structure, but also that these changes are reversible, such as the shape, surface characteristics, reaction rate, and recognition properties of the polymer. External environmental stimuli can cause such changes as: temperature, pH, ionic strength, electric field, magnetic field, light, radiation force, and the like.
In recent years, polymer membranes with pH response characteristics have shown wide application prospects in the fields of membrane separation, drug sustained release, chemical/biological sensors and the like, so the research on intelligent membranes with sensing and response functions to the change of external environmental conditions is increasingly emphasized. The pH sensitive polyurethane is a polyurethane material with the volume capable of changing with the pH and the ionic strength of the environment. The macromolecular network of the polyurethane has ionic dissociation groups, the network structure and the charge density change along with the pH of a medium, the osmotic pressure of the polyurethane is influenced, and the volume change is caused by the change of the ionic strength because of the ionic groups in the network. The polyurethane has weak acid or (and) weak base groups (such as carboxyl or amino). These groups ionize in solutions of different pH and different ionic strength, and the polyurethane then becomes charged, breaking down the hydrogen bonds in the network, resulting in a discontinuous volume change of the polyurethane.
Polyethylene glycol (PEG) is a water-soluble polymer material with high hydrophilicity and flexibility, and on one hand, the PEG can form a hydrated PEG chain with water to form stable steric hindrance and prevent platelets and the like from being adsorbed on the surface of the material; on the other hand, hydrated PEG chains have lower surface energy in water, and the formed water microflows can hinder the adhesion and deformation of proteins. In addition, the polyurethane with PEG as the soft segment has slow degradation speed, and can be used for a long time in a human body to play the role.
Pyridine is a Lewis base, the N atom of the pyridine ring being able to react with H+Combined under acidic conditions to form NH+Removal of H under alkaline conditions+. Pyridine rings are introduced into the skeleton of polyurethane to synthesize a polymer. In this system, the polymer will deprotonate and protonate with the pyridine ring, exhibiting high pH sensitivity, excellent shape memory and biocompatibility by associating and dissociating hydrogen bonds and hydrogen bond interactions between nitrogen atoms. The polyurethane has great potential for medical applications.
Patent CN1401686A discloses a preparation method of a fast-response pH sensitive polyurethane film. Synthesizing prepolymer with end capped isocyanate group through reaction of PEG, dimethylolpropionic acid and excessive isocyanate, introducing acrylate group to two ends of the prepolymer molecule, adding water solution of triethylamine to obtain polyurethane prepolymer slurry, adding proper amount of benzophenone, coating the mixture on plate glass, and ultraviolet irradiating to solidify. The synthesis method introduces carboxyl in the molecular structure of polyurethane, and the polyurethane expands in an alkaline medium, so that the degradation rate is high.
Patent CN105859995A discloses a preparation method of intelligent response type polyurethane hydrogel. And adding aliphatic isocyanate, a chain extender with an alkaline sensitive group and a cross-linking agent into the synthesized polyurethane prepolymer to generate the polyurethane hydrogel. The method is temperature and pH dual intelligent response type polyurethane hydrogel prepared by oriented polymerization, the time for the synthesized polyurethane to reach the swelling balance in deionized water is short, but the preparation method is complex, the carried dihydric alcohol with an alkaline sensitive functional group is an aromatic compound, the degradation product of the dihydric alcohol has certain toxicity to organisms, and the medical use is limited.
According to the defects of the prior art, an intelligent polyurethane urea material with slow and controlled release effect, biocompatibility, good mechanical property, slow degradation speed, simple preparation process, pH value sensitivity and induction and response functions is needed.
Disclosure of Invention
In view of the above problems in the prior art, it is an object of the present invention to provide a pH-sensitive medical polyurethaneurea. The polyethylene glycol is used as a soft segment, so that the hydrophilicity of the material is greatly improved, the deposition of platelets and proteins is hindered, the generation of thrombus is avoided, and the biocompatibility is higher. The urea-containing multi-block aliphatic diisocyanate is used as a hard segment, and the degradation product is an alkaline substance, so that acidic substances generated by degradation of the soft segment can be neutralized, and acidic inflammation at the implanted part of a human body caused by long-term implantation materials is avoided. The pyridine ring is positioned on the branched chain, so that the material can quickly respond to the change of the pH value, the material can be quickly expanded under an acidic condition, and basically does not expand under a neutral or alkaline condition, and the pyridine ring is an electron-deficient system and is not easy to be oxidized, so that the obtained polyurethane urea is resistant to yellowing.
A biodegradable pH-sensitive polyurethane urea is prepared from dihydroxypyridine terminated compound (VP- (OH)2) Mixing with double-end hydroxyl polyethylene glycol (PEG), carrying out chain extension by using diisocyanate containing a carbamido structure, and purifying to obtain pH sensitive polyurethane urea; the diisocyanate is L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate (LBL).
The structural formula of the synthesized polyurethane urea is shown as formula 1:
Figure BDA0001634133830000021
wherein:
R1：
Figure BDA0001634133830000022
R2：
Figure BDA0001634133830000031
R3：
Figure BDA0001634133830000032
m＝9～90，n＝20～100
the second purpose of the invention is to provide a preparation method of pH-sensitive medical polyurethane urea, which comprises the following steps: reacting a dihydroxypyridine-terminated compound (VP- (OH)2) Mixing with double-end hydroxyl polyethylene glycol (PEG), adding N, N-Dimethylformamide (DMF) for dissolving, adding a DMF solution of LBL for chain extension reaction, cooling to normal temperature after reaction, adding DMF for dilution, carrying out purification and sedimentation, and carrying out vacuum drying to obtain the pH value sensitive biodegradable polyurethane urea.
Preferably, VP- (OH)2The feeding molar ratio of the PEG to the PEG is 6: 1-10: 1.
Preferably, VP- (OH)2With PEG in DMFThe total concentration of (A) is 0.4-0.6 g/mL.
Preferably, the PEG has a number average molecular weight of 1000-4000 and a dispersion coefficient of 1.15-1.30.
Preferably, the chain extender is added in a manner of dripping DMF solution of the chain extender, the concentration is 0.5-1g/mL, and the dripping speed is 10 mL/min.
Preferably, the chain extender has-NCO and VP- (OH)2And the molar ratio of the PEG to the total-OH is 1.01: 1-1.05: 1.
Preferably, the chain extension reaction is carried out under dry nitrogen, the reaction temperature is 65-90 ℃, and the reaction time is 3-6 hours.
Preferably, the polyurethaneurea has a number average molecular weight of 1.0X 105～5.0×105The dispersion coefficient is 1.20 to 1.51.
Preferably, the purification method of the polyurethaneurea comprises the steps of adding DMF (dimethyl formamide) into the system to dilute the system until the concentration is 6-10 g/100mL, settling 8 times of volume of glacial ethyl ether, and drying the obtained solid at the temperature of 35-45 ℃ in vacuum to constant weight.
Preferably, VP- (OH) in the polyurethaneurea2The mass content of the PEG is 10-25 percent, and the mass content of the PEG is 15-45 percent.
The preparation method of the polyurethane urea film material comprises the steps of dissolving the obtained pH sensitive polyurethane urea material in an organic solvent to prepare a solution with the concentration of 4-7% (g/mL), volatilizing the solvent at the temperature of 15-25 ℃ for film formation under normal pressure for 60-90 h, drying at normal temperature in vacuum to obtain the polyurethane urea film material, and cutting the polyurethane urea film material into a certain shape for testing.
Preferably, the organic solvent is one or a mixture of more of chloroform, dichloromethane, acetone or dioxane.
Preferably, the swelling degree of the polyurethane urea film material is more than 180% when the pH value of the medium is 1-3, and the swelling degree of the polyurethane urea film material is less than 20% in a neutral or alkaline medium.
Dihydroxy pyridine terminated compound (VP- (OH)2) The preparation method comprises the following specific steps:
dissolving 1-thioglycerol in anhydrous dimethyl sulfoxide, drying argon to remove oxygen, adding 4-vinylpyridine and a catalyst diisopropylamine, reacting for 24-36h at normal temperature, dissolving and settling a mixture with 20-30 times volume of anhydrous ether after the reaction is finished, filtering, washing with anhydrous ether, and finally drying in vacuum at 70-90 ℃ to constant weight, wherein the yield is about 90-95%.
The reaction process is as follows:
Figure BDA0001634133830000041
preferably, the concentration of the anhydrous dimethyl sulfoxide is 1.0 g/mL;
preferably, the molar ratio of the 1-thioglycerol to the 4-vinylpyridine is 1.05:1 to 1.08: 1.
Preferably, the catalyst diisopropylamine accounts for 1-3% of the total mass of the reactants.
Dihydroxypyridine-terminated Compound (VP- (OH) obtained by the above-mentioned preparation method2) The concrete structure of (1) is as follows:
Figure BDA0001634133830000042
a preparation method of diisocyanate containing a carbamido structure comprises the following specific steps:
1) dropping 1, 4-butanediamine into L-lysine diisocyanate under the protection of dry nitrogen and mechanical stirring, and reacting at room temperature for about 1-3h to obtain a suspension A;
2) adding n-hexane into the suspension A, stirring uniformly, performing suction filtration to obtain a white solid, repeatedly washing with n-hexane until no-NCO absorption peak (2270 cm) is detected in filtrate IR-1) And drying in vacuum to constant weight to obtain white powdery diisocyanate.
The reaction formula is as follows:
Figure BDA0001634133830000043
preferably, NH is the-NCO: NH of L-lysine diisocyanate and 1, 4-butanediamine in step 1)2The molar ratio of (a) to (b) is 6:1 to 12: 1.
Preferably, the volume of n-hexane in step 2) is 4 times the volume of suspension a.
The prepared diisocyanate is L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate (LBL);
the structural formula of LBL:
Figure BDA0001634133830000044
the third purpose of the invention is to provide the application of pH value sensitive biodegradable polyurethane urea as a carrier of medicine. The polyurethaneurea contains a pyridine ring that is responsive to pH. Pyridine is a Lewis base, and under acidic conditions, the N atom of the pyridine ring is ionized and combines with H + to form NH+And the charged polyurethane urea network breaks down hydrogen bonds in the polyurethane urea network, and the repulsion of the same charge causes discontinuous volume expansion of the material. Removal of H under neutral or alkaline conditions+N on the pyridine ring and NH of the carbamate or the carbamido form a hydrogen bond which is similar to a network structure, so that the molecular chain of the polyurethane urea shrinks and the swelling degree is obviously reduced. Therefore, the swelling degree of the polyurethane urea can be effectively controlled by controlling the change of the pH value of the medium.
The polyurethane urea is prepared into medical materials such as polyurethane urea drug-loaded membrane materials, foam materials, catheter materials and the like;
according to the preparation method of the drug-loaded membrane material, an organic solvent capable of dissolving drugs is used in the preparation process of the membrane material, and the drug-loaded membrane material is prepared by the same solution volatilization method.
Preferably, the in vitro drug release amount of the polyurethane urea film material is more than 70% when the pH value of the medium is 1-3, and the in vitro drug release amount in a neutral or alkaline medium is less than 10% (the test time is 1 hour).
The invention has the beneficial effects that:
1. according to the pH-sensitive polyurethane urea provided by the invention, the pyridine ring is positioned on the branched chain, so that the material has high pH sensitivity. The pyridine ring is an alkaline sensitive group, expands in an acidic medium, has high degradation rate, basically does not expand in neutral and alkaline media, has low degradation rate, is basically not influenced by temperature, can be used as a drug carrier to be applied to the field of sustained and controlled release, and controls the release rate of the drug through the pH values of different parts of an organism to achieve the aim of positioning administration. And the pyridine ring is an electron-deficient system and is not easy to be oxidized, so that the obtained polyurethane urea is resistant to yellowing.
2. The chain extender used in the invention is multiblock aliphatic diisocyanate containing carbamido, the degradation products are lysine and aliphatic diamine, which are nontoxic and absorbable, meanwhile, the carbamido enhances the microphase separation of the material, and more carbamate groups and carbamido groups in the hard segment can form compact hydrogen bonds, thereby improving the mechanical property of the material. On the other hand, the degradation product is an alkaline substance, and can neutralize and degrade the generated acidic substance, thereby avoiding the generation of acidic inflammation.
3. The polyether is a main soft segment, so that the hydrophilicity of the material is greatly improved, the deposition of platelets and proteins is hindered, the generation of thrombus is avoided, the biocompatibility is high, the degradation speed of the polyether polyurethane urea is low, and the polyether polyurethane urea serving as a drug carrier can exist in a human body for a long time, so that the purpose of long-term administration is achieved.
4. The polyurethane urea material is prepared by a one-step method, and has the advantages of simple process, rich raw material sources and lower cost.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The present invention will be further described with reference to the following specific examples.
The following examples used dihydroxypyridine terminated Compounds (VP- (OH)2) The preparation method comprises the following steps:
dissolving 1-thioglycerol in anhydrous dimethyl sulfoxide (1.0g/mL), drying argon for deoxygenation, adding 4-vinylpyridine (the molar ratio of 1-thioglycerol to 4-vinylpyridine is 1.06:1) and a catalyst of diisopropylamine (1.5 percent of the total mass of reactants), reacting at normal temperature for 28 hours, dissolving and settling a mixture by using 20 times of volume of anhydrous ether after the reaction is finished, filtering, washing by using the anhydrous ether, and finally drying in vacuum at 75 ℃ to constant weight to obtain the yield of about 92 percent.
VP-(OH)2Is/are as follows1H NMR structural characterization results:
1H NMR(CDCl3，400MHz，ppm)：2.51(t,1H,S-CH 2-CH),2.67(t,1H,S-CH 2-CH),2.85(m,4H,C-CH 2-CH 2),3.37(q,2H,CH 2-OH),3.58(q,1H,CH-OH),4.62(t,1H,CH2-OH),4.82(d,1H,CH-OH) 7.27, 8.47(4H, pyridine ring).
The preparation method of the diisocyanate chain extender containing a carbamido structure adopted in the following examples is as follows:
the preparation method of LBL comprises the following steps: under the protection of dry nitrogen and mechanical stirring, 1, 4-butanediamine is added dropwise to L-lysine diisocyanate (-NCO: -NH)21: 8, molar ratio) at room temperature for 2h, adding four times of volume of n-hexane into the reaction product, stirring uniformly, performing suction filtration to obtain a white solid, and repeatedly washing the white solid with n-hexane until no-NCO absorption peak (2270 cm) is detected in filtrate IR-1) And vacuum drying to constant weight to obtain white powdery LBL.
Of LBL1H NMR structural characterization results:
1H NMR(DMSO-D6,400MHz,ppm):1.27-1.32(m,10H，CH 3CH2and CH 2CH2CHNCO)，1.52-1.55(m,8H, 2CHCH2NH),1.75(q，4H, 2CHCHNCO),3.08-3.16(t,8H, 2CHNH),4.08-4.15(m,6H, CH-NCO and CH)3C 2H)，5.95-6.04(br,NH)。
Example 1
5.370g (30mmol) of dihydroxypyridine terminated compound (VP- (OH)2) With 5.0g (5mmol) of polyethylene glycol (PEG, M)n1000), adding N, N-Dimethylformamide (DMF) to dissolve (0.5g/mL), heating the reaction system to 80 ℃, dropwise adding LBL (35.7mmol) DMF solution (1.0g/mL), keeping the temperature for continuing to react for 4.0h after the dropwise adding is finished, reducing the temperature to normal temperature, then adding DMF to prepare a solution with the concentration of about 10%, precipitating by 8 times of volume of ethyl glacial ether, and drying the obtained solid in vacuum at 35 ℃.
Dissolving the solid in organic solvent chloroform to prepare a drug-loaded membrane material with the concentration of 6.0% (g/mL), volatilizing a polytetrafluoroethylene membrane at the temperature of 25 ℃ under normal pressure for 80h, taking the membrane off the membrane, drying at normal temperature in vacuum to obtain a pH-sensitive medical polyurethane-urea membrane material I, and preparing the drug-loaded membrane material by the same method.
Example 2
8.950g (50mmol) of dihydroxypyridine terminated compound (VP- (OH)2) With 5.0g (5mmol) of polyethylene glycol (PEG, M)n1000), adding N, N-Dimethylformamide (DMF) to dissolve (0.5g/mL), heating the reaction system to 85 ℃, dropwise adding LBL (56.1mmol) DMF solution (1.0g/mL), keeping the temperature for continuing to react for 3.5h after the dropwise adding is finished, reducing the temperature to normal temperature, then adding DMF to prepare a solution with the concentration of about 10%, precipitating by 8 times of volume of ethyl glacial ether, and drying the obtained solid in vacuum at 35 ℃.
Dissolving the solid in organic solvent chloroform to prepare a solution with a concentration of 5.5% (g/mL), volatilizing a polytetrafluoroethylene membrane at 25 ℃ under normal pressure for 80h, taking the membrane off the membrane, drying at normal temperature in vacuum to obtain a pH-sensitive medical polyurethane-urea membrane material II, and preparing the drug-loaded membrane material by the same method.
Example 3
7.160g (40mmol) of dihydroxypyridine terminated compound (VP- (OH)2) And 10.0g (5mmol) of polyethylene glycol (PEG, M)n2000), adding N, N-Dimethylformamide (DMF) to dissolve (0.6g/mL), heating the reaction system to 90 ℃, dropwise adding LBL (51.0mmol) DMF solution (1.0g/mL), keeping the temperature for continuing to react for 3.0h after the dropwise adding is finished, cooling to the normal temperature, adding DMF to prepare a solution with the concentration of about 10%, settling by 8 times of volume of glacial ethyl ether, and drying the obtained solid in vacuum at 35 ℃.
Dissolving the solid in organic solvent chloroform to prepare a drug-loaded membrane material with the concentration of 5.5% (g/mL), volatilizing a polytetrafluoroethylene membrane at the temperature of 25 ℃ under normal pressure for 80h, taking the membrane off the membrane, drying at normal temperature in vacuum to obtain a pH-sensitive medical polyurethane-urea membrane material III, and preparing the drug-loaded membrane material by the same method.
Example 4
7.160g (40mmol) of dihydroxypyridine terminated compound (VP- (OH)2) With 20.0g (5mmol) of polyethylene glycol (PEG, M)n3000), adding N, N-Dimethylformamide (DMF) to dissolve (0.6g/mL), heating the reaction system to 75 ℃, dropwise adding LBL (45.9mmol) DMF solution (1.0g/mL), keeping the temperature for continuing to react for 4.5h after the dropwise adding is finished, cooling to the normal temperature, adding DMF to prepare a solution with the concentration of about 10%, precipitating by 8 times of volume of ethyl glacial ether, and drying the obtained solid in vacuum at 35 ℃.
Dissolving the solid in organic solvent chloroform to prepare a drug-loaded membrane material with the concentration of 6.0% (g/mL), volatilizing a polytetrafluoroethylene membrane at the temperature of 25 ℃ under normal pressure for 80h, taking the membrane off the membrane, and then drying at normal temperature and vacuum to obtain the pH-sensitive medical polyurethane-urea membrane material IV.
Example 5
Under dry nitrogen, 5.37g (30mmol) of dihydroxypyridine terminated compound (VP- (OH)2) With 20.0g (5mmol) of polyethylene glycol (PEG, M)n4000), adding N, N-Dimethylformamide (DMF), dissolving (0.5g/mL), heating the reaction system to 80 ℃, dropwise adding LBL (35.7mmol) DMF solution (1.0g/mL), keeping the temperature for continuous reaction for 3.8h after the dropwise adding is finished, cooling to the normal temperature, adding DMF to prepare a solution with the concentration of about 10%, precipitating by 8 times of volume of glacial ethyl ether, and drying the obtained solid in vacuum at 35 ℃.
Dissolving the solid in organic solvent chloroform to prepare a drug-loaded membrane material V with the concentration of 6.0% (g/mL), volatilizing a polytetrafluoroethylene membrane at the temperature of 25 ℃ under normal pressure for 80h, taking the membrane off the membrane, and then drying at normal temperature in vacuum to obtain the pH-sensitive medical polyurethane-urea membrane material.
The following analytical methods were used for all examples unless otherwise indicated.
Molecular weight and molecular weight distribution: polyurethaneurea molecular weight and molecular weight distribution were measured using an Alpha gel chromatograph (GPC) from Water corporation, USA, and 4mg of the sample was dissolved in 2mL of tetrahydrofuran, filtered into a dedicated chromatographic flask using a 0.4 μm filter head, and the mobile phase rate was 0.5mL/min, the temperature of the column box was set at 35 ℃, and the standard was monodisperse polystyrene.
And (3) testing the swelling degree: a10 mm by 20mm sample is cut from the film and has a mass m0Soaking the materials in different pH media at room temperature, and observing the change of the appearance of the materials along with the soaking time. After 30 minutes of soaking, the membrane is taken out, and the surface moisture is quickly wiped off by filter paper, wherein the mass is m1. And (3) calculating the swelling degree of the film according to a formula: swelling degree%1-m0)/m0×100。
Preparation of drug-loaded membrane material and drug release test: dissolving the ceftibuten in chloroform, dissolving the polyurethaneurea, preparing a drug-loaded membrane material by solvent volatilization (the dosage of the ceftibuten is 1.2 percent of the mass of the polyurethaneurea), respectively putting the drug-loaded polyurethaneurea membrane material into a certain amount of solution with the pH value of 1.5, 7.5 and 9.5, taking the same amount of solution after 1 hour, measuring the absorbance of the solution by an ultraviolet spectrophotometry, comparing the absorbance with a standard curve, and calculating the drug cumulative release (%) of the drug-loaded membrane material.
The composition and properties of one of the pH sensitive polyurethaneurea materials of examples 1-5 are shown in Table 1.
TABLE 1 Properties of the polyurethaneureas
Figure BDA0001634133830000081
*The content of PEG is polyurethane ureaThe mass content of (A);
**VP(OH)2the content of (a) is the mass content in the polyurethaneurea;
***is the amount of released ceftibuten in 1 h.
As can be seen from Table 1, the polyurethaneurea prepared by the process provided by this patent has a relatively high molecular weight. The mass content of the terminal dihydroxypyridine compound in the material is 10-25%, and the pH sensitivity of the material is greatly improved along with the increase of the content of the terminal dihydroxypyridine compound. In vitro drug release is related to the swelling degree of the material, the greater the swelling degree, the more in vitro release. The samples in the examples of this patent have a swelling degree of more than 180% at pH 1.5 and less than 20% at pH 7.5 and pH 9.5, indicating that the polyurethaneurea has excellent pH sensitivity. When the pH value of the medium is 1.5, the release amount of the ceftibuten in 1h is more than 70%, and the release amount of the drug in neutral and alkaline media is less than 10% at the same time, so that the material can be used as a drug carrier to control the release rate of the drug by changing the pH value of the environment, and can be applied to the field of sustained and controlled release. The material is polyether polyurethane urea, has high biocompatibility and biodegradability, and degradation products can be absorbed, so that the material can be applied to human bodies as a drug carrier.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims (18)

1. A pH sensitive medical polyurethaneurea, characterized by:
the structural formula of the polyurethane urea is shown as formula 1:
Figure FDA0002650962400000011
wherein:
R1：
Figure FDA0002650962400000012
R2：
Figure FDA0002650962400000013
R3：
Figure FDA0002650962400000014
m is 9-90, n is 20-100; the number average molecular weight of the polyurethaneurea is 1.0X 105～5.0×105The dispersion coefficient is 1.20-1.51;
the preparation method of the polyurethane urea comprises the following steps: mixing a terminal dihydroxypyridine compound and double-terminal hydroxyl polyethylene glycol, adding N, N-dimethylformamide to dissolve, adding N, N-dimethylformamide solution of L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate to perform chain extension reaction, cooling to normal temperature after reaction, adding N, N-dimethylformamide to dilute, and performing purification, sedimentation and vacuum drying to obtain pH sensitive medical polyurethane urea; the feeding molar ratio of the terminal dihydroxypyridine compound to the terminal hydroxyl polyethylene glycol is 6: 1-10: 1; the molar ratio of-NCO of the chain extender L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate to the sum of-OH of the terminal dihydroxypyridine compound and the terminal hydroxyl polyethylene glycol is 1.01: 1-1.05: 1;
the specific structure of the dihydroxypyridine-terminated compound is as follows:
Figure FDA0002650962400000015
l-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate has the following structural formula:
Figure FDA0002650962400000016
2. the pH-sensitive medical polyurethaneurea according to claim 1, wherein: the total concentration of the N, N-dimethylformamide of the terminal dihydroxypyridine compound and the terminal hydroxyl polyethylene glycol is 0.4-0.6 g/mL.
3. The pH-sensitive medical polyurethaneurea according to claim 1, wherein: the number average molecular weight of the double-end hydroxyl polyethylene glycol is 1000-4000, and the dispersion coefficient is 1.15-1.30.
4. The pH-sensitive medical polyurethaneurea according to claim 1, wherein: the chain extender is added in a mode of dripping N, N-dimethylformamide solution of the chain extender, the concentration is 0.5-1g/mL, and the dripping speed is 10 mL/min.
5. The pH-sensitive medical polyurethaneurea according to claim 1, wherein: and the chain extension reaction is carried out under dry nitrogen, the reaction temperature is 65-90 ℃, and the reaction time is 3-6 h.
6. The pH-sensitive medical polyurethaneurea according to claim 1, wherein: the purification method of the polyurethane urea comprises the steps of adding N, N-dimethylformamide into a system to dilute the polyurethane urea until the concentration is 6-10 g/100mL, settling 8 times of volume of glacial ethyl ether, and drying the obtained solid at the temperature of 35-45 ℃ in vacuum until the weight is constant.
7. The pH-sensitive medical polyurethaneurea according to claim 1, wherein: the mass content of the terminal dihydroxy pyridine compound in the polyurethane urea is 10-25%, and the mass content of the terminal hydroxy polyethylene glycol is 15-45%.
8. The pH-sensitive medical polyurethaneurea according to claim 1, wherein: a preparation method of a dihydroxyl-terminated pyridine compound comprises the following specific steps:
dissolving 1-thioglycerol in anhydrous dimethyl sulfoxide, drying argon gas for removing oxygen, adding 4-vinylpyridine and a catalyst diisopropylamine, reacting for 24-36h at normal temperature, dissolving the mixture with 20-30 times volume of anhydrous ether for settling after the reaction is finished, filtering, washing with anhydrous ether, and finally drying in vacuum at 70-90 ℃ to constant weight.
9. The pH-sensitive medical polyurethaneurea according to claim 8, wherein: the concentration of anhydrous dimethyl sulfoxide was 1.0 g/mL.
10. The pH-sensitive medical polyurethaneurea according to claim 8, wherein: the catalyst diisopropylamine accounts for 1-3% of the total mass of the reactants.
11. The pH-sensitive medical polyurethaneurea according to claim 8, wherein: the molar ratio of the 1-thioglycerol to the 4-vinylpyridine is 1.05: 1-1.08: 1.
12. The pH-sensitive medical polyurethaneurea according to claim 1, wherein: the preparation method of the L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate comprises the following specific steps:
1) dropping 1, 4-butanediamine into L-lysine diisocyanate under the protection of dry nitrogen and mechanical stirring, and reacting at room temperature for 1-3h to obtain a suspension A;
2) adding normal hexane into the suspension A, stirring uniformly, performing suction filtration to obtain a white solid, repeatedly washing the white solid with the normal hexane until no-NCO absorption peak is detected in filtrate IR, and performing vacuum drying to constant weight to obtain white powdery L-lysine diisocyanate-1, 4-butanediamine-L-lysine diisocyanate.
13. The pH-sensitive medical polyurethaneurea according to claim 12, wherein: NH is the ratio of-NCO to-NH of L-lysine diisocyanate and 1, 4-butanediamine in the step 1)2The molar ratio of (a) to (b) is 6:1 to 12: 1.
14. The pH-sensitive medical polyurethaneurea according to claim 12, wherein: the volume of the n-hexane in the step 2) is 4 times of the volume of the suspension A.
15. A preparation method of a polyurethane urea film material is characterized by comprising the following steps: the pH-sensitive medical polyurethane-urea material of claim 1 is dissolved in an organic solvent to prepare a solution with the concentration of 4-7% g/mL, and the solution is volatilized to form a film to prepare the polyurethane-urea film material.
16. The method for preparing a polyurethaneurea film material as claimed in claim 15, wherein: the volatilization temperature of the solvent is 15-25 ℃, the solvent is volatilized for 60-90 h under normal pressure, and then the polyurethane urea film material is obtained by drying in vacuum at normal temperature.
17. The method for preparing a polyurethaneurea film material as claimed in claim 15, wherein: the organic solvent is one or a mixture of more of trichloromethane, dichloromethane, acetone or dioxane.
18. Use of the pH-sensitive medical polyurethaneurea of claim 1 as a carrier for a pharmaceutical.
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