CN108530606A - A kind of pH sensibility medical polyurethane urea material and preparation method thereof - Google Patents
A kind of pH sensibility medical polyurethane urea material and preparation method thereof Download PDFInfo
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- CN108530606A CN108530606A CN201810353952.XA CN201810353952A CN108530606A CN 108530606 A CN108530606 A CN 108530606A CN 201810353952 A CN201810353952 A CN 201810353952A CN 108530606 A CN108530606 A CN 108530606A
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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
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- 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
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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
- C08G18/30—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 kind of pH sensibility medical polyurethane urea materials and preparation method thereof, polyurethane-urea is mixed by a kind of end dihydroxy-pyridine compound with hydroxyl carbowax, N is added, after the dissolving of N dimethylformamides, chain extension is carried out with the diisocyanate containing urea groups again, it is purified to obtain pH sensitive polyurethane ureas；The diisocyanate is 1,4 butanediamine L lysine diisocyanates of L lysine diisocyanates.The pyridine groups of the polyurethane-urea side chain are lewis bases, in acid condition, so that hydrogen bond in polyurethane-urea network is disintegrated, cause material that discontinuous volume expansion occurs.H is removed under neutral or basic conditions+, the N and NH of carbamate or urea groups on pyridine ring forms hydrogen bond, is similar to network structure so that polyurethane-urea strand is shunk, and swellbility is decreased obviously.Therefore by controlling the variation of PH values, the swellbility of polyurethane-urea can effectively be controlled.
Description
Technical field
The invention belongs to biomaterial preparing technical fields, more particularly to Intelligent medical polymeric material field, specifically relate to
And to a kind of preparation method of pH sensibility medical polyurethane urea.
Background technology
Intelligent macromolecule material be it is a kind of can make corresponding response to the stimulation of ambient enviroment, while again along with itself
The material of certain change of properties.In 21 century, the application of intelligent polyurethane is widely paid close attention to by people, this intelligence polyurethane
Material is widely used in bio-separation, actuator, drug controlled release and regenerative medicine field.Intelligent polyurethane
Uniqueness, which is not singly subtle stimulation, so that self structure is changed, and these variations are reversible, such as polymer
Shape, surface characteristic, reaction speed and recognition performance etc..The stimulation of external environment can cause these variations such as：Temperature, pH
Value, ionic strength, electric field, magnetic field, illumination, radiant force etc..
In recent years, the polymeric membrane with pH response characteristics is in necks such as UF membrane, medicament slow release and chemical/biological sensors
Domain all shows wide application prospect, so this kind of smart membrane to extraneous changes in environmental conditions with induction and response function
Research be paid more and more attention.PH sensitive polyurethanes are the polyurethane materials that volume energy changes with environment pH, ionic strength.This
In class polyurethane macromolecular network there is ionic dissociation groups, network structure and charge density to change with medium pH, and to poly-
The osmotic pressure of urethane has an impact, simultaneously as there is ionic group in network, the variation of ionic strength also causes volume change.It is poly-
Have in urethane weak acid or (and) weak base group (such as carboxyl or amino).These groups are molten different pH value and different ionic strength
Liquid is ionized, and then polyurethane carries charge, and hydrogen bond in network is made to disintegrate, and causes polyurethane that discontinuous volume occurs and becomes
Change.
Polyethylene glycol (PEG) is that have very high hydrophily and flexible water-soluble high-molecular material, on the one hand can be with
Hydration PEG chains are formed with water, form stable steric hindrance, platelet etc. is adsorbed on material surface；On the other hand, it is hydrated
There is PEG chains lower surface energy, the water miniflow of formation can hinder the adherency and deformation of protein in water.Also, with PEG
As the polyurethane of soft segment, degradation speed is slow, can be long-term used in human body, plays its effect.
Pyridine is lewis base, and the N atoms of pyridine ring can be with H+In conjunction with forming NH in acid condition+, in alkaline item
H is removed under part+.Pyridine ring is introduced into the skeleton of polyurethane, a kind of polymer is synthesized.In such a system, polymer will be with pyrrole
Phenazine ring deprotonation and protonation reaction are shown by associating and detaching the interaction of hydrogen bond between hydrogen bond and nitrogen-atoms
High pH sensibility, excellent shape memory and biocompatibility.The polyurethane has prodigious medical applications potentiality.
Patent CN1401686A discloses a kind of preparation method of the pH sensitive polyurethane films of fast-response.By PEG,
Dihydromethyl propionic acid reacts the prepolymer for carrying out synthesizing isocyanate base sealing end with excessive isocyanates, at prepolymer molecule both ends
It introduces acrylate-based, is added in the aqueous solution of triethylamine, obtains polyurethane prepolymer slurry, be then added the two of proper proportion
Benzophenone is applied to plate glass, through UV radiation curing at thin with this mixture.The synthetic method is in polyurethane molecular
Carboxyl is introduced in structure, is expanded in alkaline medium, and degradation rate is fast.
Patent CN105859995A discloses a kind of preparation method of intelligent response type polyurethane hydrogel.To the poly- of synthesis
Aliphatic isocyanates, chain extender and crosslinking agent with alkaline-sensitive group are added in urethane prepolymer, generates polyurethane water-setting
Glue.This kind of method is the temperature prepared by stereospecfic polymerization and the dual intelligent response type polyurethane hydrogels of pH, and synthesize
The time that polyurethane reaches swelling equilibrium in deionized water is short, but preparation method is complicated, and the alkaline-sensitive of institute's band
The dihydric alcohol of functional group is aromatic compound, and catabolite has certain toxicity to organism, use medically by
To limitation.
According to above-mentioned the deficiencies in the prior art, there is an urgent need for a kind of with slow controlled-release effect, biocompatibility, mechanicalnesses at present
Energy is good, degradation speed is slow, intelligent polyurethane-urea material of the simple pH sensitive of preparation process with induction and response function.
Invention content
For the above-mentioned prior art the problem of, the object of the present invention is to provide a kind of medical poly- ammonia of pH sensibility for this
Ester urea.Wherein polyethylene glycol greatly improves the hydrophily of material as soft segment, hinders the deposition of blood platelet and protein,
The generation of thrombus is avoided, there is higher biocompatibility.Made using more blocked aliphatic diisocyanate containing urea groups
For hard section, catabolite is alkaline matter, can neutralize the acidic materials that soft segment degradation generates, avoid as being chronically implanted material
Human body implant site is set to generate acid inflammation.Pyridine ring is located at branch, and material is enable to respond the change of pH value faster, the material
Expect rapid expanding under acid condition, does not expand substantially under neutral or basic conditions, and pyridine ring is short of electricity subsystem, is not easy
Aoxidized, so as to get polyurethane-urea color inhibition.
A kind of pH sensitive biodegradable polyurethane urea, by a kind of end dihydroxy-pyridine compound (VP- (OH)2) with
Hydroxyl carbowax (PEG) mixes, then carries out chain extension with the diisocyanate of the structure containing urea groups, purified to obtain pH sensitivities
Property polyurethane-urea；The diisocyanate is L-lysine diisocyanate -1,4- butanediamine-L-lysine diisocyanate
(LBL)。
The structural formula of the polyurethane-urea of synthesis such as formula 1：
Wherein：
R1：
R2：
R3：
M=9~90, n=20~100
Second object of the present invention is to provide a kind of preparation method of pH sensibility medical polyurethane urea, specific steps
For：By end dihydroxy-pyridine compound (VP- (OH)2) and hydroxyl carbowax (PEG) mixing, N, N- dimethyl methyls is added
After amide (DMF) dissolving, the DMF solution that LBL is added carries out chain extending reaction, and room temperature is down to after reaction, DMF dilutions is added, through pure
Change sedimentation, vacuum drying obtains pH sensitive biodegradable polyurethane urea.
Preferably, VP- (OH)2With the molar ratio 6 of PEG:1~10:1.
Preferably, VP- (OH)2It is 0.4-0.6g/mL with total concentrations of the PEG in DMF.
Preferably, the number-average molecular weight of PEG is 1000-4000, and the coefficient of dispersion is 1.15~1.30.
Preferably, the feed postition of chain extender is the DMF solution that chain extender is added dropwise, a concentration of 0.5-1g/mL, rate of addition
For 10mL/min.
Preferably ,-the NCO of chain extender and VP- (OH)2Molar ratio with the-OH summations of PEG is 1.01:1~1.05:1.
Preferably, chain extending reaction carries out under drying nitrogen, and reaction temperature is 65~90 DEG C, and the reaction time is 3~6h.
Preferably, the number-average molecular weight of polyurethane-urea is 1.0 × 105~5.0 × 105, the coefficient of dispersion is 1.20~1.51.
Preferably, the way of purification of polyurethane-urea is that DMF is added into system to be diluted to a concentration of 6~10g/100mL, 8
The sedimentation of times volume ice ether, 35~45 DEG C of normal-temperature vacuums of obtained solid are dried to constant weight.
Preferably, the VP- in polyurethane-urea (OH)2Mass content be 10-25%, the mass content of PEG is 15-
45%.
The preparation method of polyurethane-urea membrane material is that obtained pH sensitive polyurethane urea materials are dissolved in organic solvent
In, it is made into the solution of a concentration of 4~7% (g/mL), being volatilized into film preparation through solvent obtains polyurethane film material, solvent volatilization temperature
Degree is 15~25 DEG C, and normal pressure 60~90h of volatilization is dried by normal-temperature vacuum, obtained polyurethane-urea membrane material, be cut into definite shape
It is tested.
Preferably, the organic solvent is chloroform, dichloromethane, one kind of acetone or dioxane or in which several
Mixed solvent.
Preferably, swellbility of the polyurethane-urea membrane material when medium pH is 1~3 is more than 180%, is situated between in neutral or alkalinity
Swellbility is less than 20% in matter.
A kind of end dihydroxy-pyridine compound (VP- (OH)2) preparation method, the specific steps are：
1- thioglycerols are dissolved in anhydrous dimethyl sulfoxide, 4-vinylpridine and catalysis is added in dry argon gas deoxygenation
Agent diisopropylamine reacts 24-36h at normal temperatures, after reaction, the anhydrous ether of 20~30 times of volumes of mixture is molten heavy
Drop, filtering, anhydrous ether washing are finally dried under vacuum to constant weight, yield is about 90-95% at 70-90 DEG C.
Reaction process is：
Preferably, a concentration of 1.0g/mL of anhydrous dimethyl sulfoxide；
Preferably, 1- thioglycerols and 4-vinylpridine molar ratio are 1.05:1~1.08:1.
Preferably, catalyst diisopropylamine accounts for the 1~3% of reactant gross mass.
The end dihydroxy-pyridine compound (VP- (OH) that above-mentioned preparation method obtains2) concrete structure be：
A kind of preparation method of the diisocyanate containing urea groups structure, the specific steps are：
1) under drying nitrogen protection and mechanical agitation, Putriscine is added drop-wise in L-lysine diisocyanate, room
After the lower reaction of temperature about 1-3h, suspending liquid A is obtained；
2) n-hexane is added into suspending liquid A, after stirring evenly, suction filtration obtains white solid, is washed repeatedly with n-hexane
To filtrate IR detections without-NCO absorption peaks (2270cm-1), it is dried under vacuum to constant weight, obtains white powder diisocyanate.
Reaction equation is：
Preferably, in step 1) L-lysine diisocyanate and Putriscine-NCO:NH2Molar ratio be 6:1
~12:1.
Preferably, the volume of n-hexane is 4 times of suspending liquid A volume in step 2).
The diisocyanate being prepared is L-lysine diisocyanate -1,4- butanediamine-L-lysine diisocyanate
Ester (LBL)；
The structural formula of LBL：
A kind of load third object of the present invention is to provide pH sensitive biodegradable polyurethane urea as drug
Application in body.The polyurethane-urea contains the pyridine ring responded to pH.Pyridine is lewis base, in acid condition, pyridine ring
N atomizing/ionizings, combined to form NH with H++, charge is carried, so that hydrogen bond in polyurethane-urea network is disintegrated, and like charges
Repulsive interaction, cause material that discontinuous volume expansion occurs.H is removed under neutral or basic conditions+, the N on pyridine ring
Hydrogen bond is formed with the NH of carbamate or urea groups, is similar to network structure so that polyurethane-urea strand is shunk, and swellbility is bright
It is aobvious to decline.Therefore by controlling the variation of PH values, the swellbility of polyurethane-urea can effectively be controlled.
The polyurethane-urea is prepared as the medical materials such as polyurethane-urea medicine carrying membrane material, foamed material, conduit material；
The preparation method of the medicine carrying membrane material, being used in membrane material preparation process can be dissolved with the organic molten of drug
Medicine carrying membrane material is prepared by same solution evaporation method in agent.
Preferably, vitro drug release amount of the polyurethane-urea membrane material when medium pH is 1~3 is more than 70%, in neutrality
Or vitro drug release amount is less than 10% (testing time is 1 hour) in alkaline medium.
Beneficial effects of the present invention：
1. a kind of pH sensitive polyurethanes urea provided by the invention, pyridine ring are located on branch, material is made to have high pH quick
Perception.Pyridine ring is alkaline-sensitive group, is expanded in acid medium, and degradation rate is fast, basic in neutral and alkaline medium
It does not expand, degradation speed is slow, and this pH sensibility is not affected by temperature substantially, can be used as pharmaceutical carrier and is applied to slow controlled release
Field is controlled the rate of release of drug by the pH value of organism different parts, achievees the purpose that site-specific delivery of drugs.And pyridine ring
Be short of electricity subsystem, be not easy to be aoxidized, so as to get polyurethane-urea color inhibition.
2. the chain extender used in the present invention is more blocked aliphatic diisocyanate containing urea groups, catabolite is to rely ammonia
Acid and aliphatic diamine, it is nontoxic, absorbable, while urea groups enhances the microphase-separated of material, and ammonia more in hard section
Carbamate base and urea groups can form fine and close hydrogen bond, to improve the mechanical performance of material.On the other hand, catabolite
For alkaline matter, the acidic materials that degradation generates can be neutralized, the generation of acid inflammation is avoided.
3. polyethers is main soft segment in the present invention, the hydrophily of material is greatly improved, blood platelet and protein are hindered
Deposition, avoid the generation of thrombus, there is higher biocompatibility, and polyether polyurethane urea degradation speed is slow, makees
It can achieve the purpose that long term administration with long-term existence in human body for pharmaceutical carrier.
4. the polyurethane-urea material is prepared by one-step method, simple for process, raw material sources are abundant, and cost is relatively low.
Specific implementation mode
It is noted that following detailed description is all illustrative, it is intended to provide further instruction to the application.Unless another
It indicates, all technical and scientific terms used herein has usual with the application person of an ordinary skill in the technical field
The identical meanings of understanding.
It should be noted that term used herein above is merely to describe specific implementation mode, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singulative
It is also intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation, device, component and/or combination thereof.
With reference to specific embodiment, the invention will be further described.
The end dihydroxy-pyridine compound (VP- (OH) that following embodiment uses2) preparation method be：
1- thioglycerols are dissolved in anhydrous dimethyl sulfoxide (1.0g/mL), 4- vinylpyridines are added in dry argon gas deoxygenation
(1- thioglycerols are 1.06 with 4-vinylpridine molar ratio for pyridine:1) and catalyst diisopropylamine (reactant gross mass
1.5%) 28h, is reacted at normal temperatures, after reaction, by the molten sedimentation of anhydrous ether of 20 times of volumes of mixture, filtering, nothing
Water ether washs, and constant weight is finally dried under vacuum at 75 DEG C, yield is about 92%.
VP-(OH)2's1H 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 rings).
The preparation method for the diisocyanate chain extender containing urea groups structure that following embodiment uses for：
The preparation method of LBL is：Under drying nitrogen protection and mechanical agitation, Putriscine is added drop-wise to L-lysine two
(- NCO in isocyanates:-NH2=8:1, molar ratio), after reacting 2h at room temperature, tetraploid product is being added into reaction product just
Hexane, after stirring evenly, suction filtration obtains white solid, is washed repeatedly to filtrate IR detections without-NCO absorption peaks with n-hexane
(2270cm-1), it is dried under vacuum to constant weight, obtains white powder LBL.
LBL's1H 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,CH2 CH2NH), 1.75 (q, 4H,CH2 CHNCO),3.08-3.16(t,8H,CH2 NH),4.08-4.15(m,6H,
CH-NCO and CH3CH2 ), 5.95-6.04 (br, NH)。
Embodiment 1
Under drying nitrogen protection, by the ends 5.370g (30mmol) dihydroxy-pyridine compound (VP- (OH)2) and 5.0g
(5mmol) polyethylene glycol (PEG, Mn=1000) it mixes, n,N-Dimethylformamide (DMF) is added and dissolves (0.5g/mL), reaction
System is warming up to 80 DEG C, is added dropwise to the DMF solution (1.0g/mL) of LBL (35.7mmol), keeps temperature to continue after being added dropwise anti-
4.0h is answered, room temperature is down to, DMF is then added and is configured to the solution that concentration is about 10%, 8 times of volume ice ether settle, and gained is solid
35 DEG C of vacuum drying of body.
Solid is dissolved in organic solvents, chloroform, a concentration of 6.0% (g/mL) is made into, is existed using polytetrafluoroethylene film tool
Film is removed from film tool, is dried by normal-temperature vacuum, obtain pH sensibility medical polyurethane urea membrane materials by 25 DEG C of normal pressures volatilization 80h
Expect that I, same procedure prepare medicine carrying membrane material.
Embodiment 2
Under drying nitrogen protection, by the ends 8.950g (50mmol) dihydroxy-pyridine compound (VP- (OH)2) and 5.0g
(5mmol) polyethylene glycol (PEG, Mn=1000) it mixes, n,N-Dimethylformamide (DMF) is added and dissolves (0.5g/mL), reaction
System is warming up to 85 DEG C, is added dropwise to the DMF solution (1.0g/mL) of LBL (56.1mmol), keeps temperature to continue after being added dropwise anti-
3.5h is answered, room temperature is down to, DMF is then added and is configured to the solution that concentration is about 10%, 8 times of volume ice ether settle, and gained is solid
35 DEG C of vacuum drying of body.
Solid is dissolved in organic solvents, chloroform, a concentration of 5.5% (g/mL) is made into, is existed using polytetrafluoroethylene film tool
Film is removed from film tool, is dried by normal-temperature vacuum, obtain pH sensibility medical polyurethane urea membrane materials by 25 DEG C of normal pressures volatilization 80h
Material II, same procedure prepares medicine carrying membrane material.
Embodiment 3
Under drying nitrogen protection, by the ends 7.160g (40mmol) dihydroxy-pyridine compound (VP- (OH)2) and 10.0g
(5mmol) polyethylene glycol (PEG, Mn=2000) it mixes, n,N-Dimethylformamide (DMF) is added and dissolves (0.6g/mL), reaction
System is warming up to 90 DEG C, is added dropwise to the DMF solution (1.0g/mL) of LBL (51.0mmol), keeps temperature to continue after being added dropwise anti-
3.0h is answered, room temperature is down to, DMF is then added and is configured to the solution that concentration is about 10%, 8 times of volume ice ether settle, and gained is solid
35 DEG C of vacuum drying of body.
Solid is dissolved in organic solvents, chloroform, a concentration of 5.5% (g/mL) is made into, is existed using polytetrafluoroethylene film tool
Film is removed from film tool, is dried by normal-temperature vacuum, obtain pH sensibility medical polyurethane urea membrane materials by 25 DEG C of normal pressures volatilization 80h
Material III, same procedure prepares medicine carrying membrane material.
Embodiment 4
Under drying nitrogen protection, by the ends 7.160g (40mmol) dihydroxy-pyridine compound (VP- (OH)2) and 20.0g
(5mmol) polyethylene glycol (PEG, Mn=3000) it mixes, n,N-Dimethylformamide (DMF) is added and dissolves (0.6g/mL), reaction
System is warming up to 75 DEG C, is added dropwise to the DMF solution (1.0g/mL) of LBL (45.9mmol), keeps temperature to continue after being added dropwise anti-
4.5h is answered, room temperature is down to, DMF is then added and is configured to the solution that concentration is about 10%, 8 times of volume ice ether settle, and gained is solid
35 DEG C of vacuum drying of body.
Solid is dissolved in organic solvents, chloroform, a concentration of 6.0% (g/mL) is made into, is existed using polytetrafluoroethylene film tool
Film is removed from film tool, is dried by normal-temperature vacuum, obtain pH sensibility medical polyurethane urea membrane materials by 25 DEG C of normal pressures volatilization 80h
Material IV, same procedure prepares medicine carrying membrane material.
Embodiment 5
Under drying nitrogen protection, by the ends 5.37g (30mmol) dihydroxy-pyridine compound (VP- (OH)2) and 20.0g
(5mmol) polyethylene glycol (PEG, Mn=4000) it mixes, n,N-Dimethylformamide (DMF) is added and dissolves (0.5g/mL), reaction
System is warming up to 80 DEG C, is added dropwise to the DMF solution (1.0g/mL) of LBL (35.7mmol), keeps temperature to continue after being added dropwise anti-
3.8h is answered, room temperature is down to, DMF is then added and is configured to the solution that concentration is about 10%, 8 times of volume ice ether settle, and gained is solid
35 DEG C of vacuum drying of body.
Solid is dissolved in organic solvents, chloroform, a concentration of 6.0% (g/mL) is made into, is existed using polytetrafluoroethylene film tool
Film is removed from film tool, is dried by normal-temperature vacuum, obtain pH sensibility medical polyurethane urea membrane materials by 25 DEG C of normal pressures volatilization 80h
Material V, same procedure prepares medicine carrying membrane material.
Following analysis method is used for all embodiments, unless otherwise stated.
Molecular weight and molecular weight distribution：It is measured using the Alpha types gel permeation chrommatograph (GPC) of Water companies of the U.S. poly-
Urethane urea molecular weight and molecualr weight distribution, 4mg samples are dissolved in 2mL tetrahydrofurans, and special chromatogram bottle is filled into 0.4 μm of filtering head
In, mobile phase rate is 0.5mL/min, and chromatograph box temperature is set as 35 DEG C, and standard specimen is monodisperse polystyrene.
Swellbility is tested：The sample of clip 10mm × 20mm from film, quality m0, it is soaked into different pH at room temperature and is situated between
Matter observes the variation of its appearance soaking time.After impregnating 30 minutes, film is taken out, surface moisture is wiped clean rapidly with filter paper,
It is m to measure its quality1.The dilation of film is calculated by formula：Swellbility %=(m1-m0)/m0×100。
The preparation of medicine carrying membrane material and drug release test：First Ceftibuten is dissolved in chloroform, is redissolved polyurethane-urea,
Medicine carrying membrane material (dosage of Ceftibuten is the 1.2% of polyurethane-urea quality) is prepared through solvent volatilization, medicine polyurethane-urea will be carried
Membrane material is respectively put into the solution of a certain amount of pH=1.5,7.5,9.5, after 1 hour, takes equivalent solution, uses ultraviolet spectrophotometry
Its absorbance is measured, is contrasted with standard curve, the drug accumulation release (%) of medicine carrying membrane material is calculated.
A kind of composition of pH sensitive polyurethanes urea material and performance are as shown in table 1 in embodiment 1-5.
The performance of 1. polyurethane-urea of table
*The content of PEG is the mass content in polyurethane-urea；
**VP(OH)2Content be polyurethane-urea in mass content；
***For the burst size of Ceftibuten in 1h.
As shown in Table 1, polyurethane-urea prepared by the method that this patent is provided has higher molecular weight.In the material
It is 10-25% to hold the mass content of dihydroxy-pyridine compound, with the increase of end dihydroxy-pyridine compounds content, the pH of material
Sensibility significantly rises.Vitro drug release is related with the swellbility of material, and swellbility is bigger, and release in vitro is more.This is specially
Swellbility of the swellbility of sample in sharp embodiment in medium pH=1.5 is more than 180%, is situated between in pH=7.5 and pH=9.5
Swellbility is less than 20% in matter, shows that the polyurethane-urea has splendid pH sensibility.When medium pH=1.5, cephalo cloth in 1h
The burst size of alkene is all higher than 70%, and the release amount of medicine under the same time in neutral and alkaline medium is less than 10%, therefore should
Material can be used as pharmaceutical carrier and change Drug controlled release rate by environment pH, so as to be applied to slow controlled release field.And
The material is polyether polyurethane urea, has higher biocompatibility, while there is biodegradable, catabolite can inhale
It receives, therefore human body is can be applied to as pharmaceutical carrier.
The foregoing is merely the preferred embodiments of the application, are not intended to limit this application, for the skill of this field
For art personnel, the application can have various modifications and variations.Within the spirit and principles of this application, any made by repair
Change, equivalent replacement, improvement etc., should be included within the protection domain of the application.
Claims (10)
1. a kind of pH sensibility medical polyurethane urea, it is characterised in that：By a kind of end dihydroxy-pyridine compound and both-end hydroxyl
Polyethylene glycol mixes, then carries out chain extension with the diisocyanate of the structure containing urea groups, purified to obtain pH sensitive polyurethane ureas；Institute
It is L-lysine diisocyanate -1,4- butanediamine-L-lysine diisocyanate to state diisocyanate；
The structural formula of the polyurethane-urea of synthesis such as formula 1：
Wherein：
R1：
R2：
R3：
M=9~90, n=20~100.
2. a kind of preparation method of pH sensibility medical polyurethane urea, it is characterised in that：The specific steps are：By end dihydroxy-pyridine
The DMF solution of LBL is added after n,N-Dimethylformamide (DMF) dissolving is added in compound and hydroxyl carbowax mixing
Chain extending reaction is carried out, room temperature is down to after reaction, DMF dilutions are added, purified sedimentation, vacuum drying, which obtains pH sensitive, to give birth to
Object degradable polyurethane urea；
Preferably, it is 0.4-0.6g/mL to hold dihydroxy-pyridine compound and the DMF total concentrations of polyethylene glycol；
Preferably, the number-average molecular weight of PEG is 1000-4000, and the coefficient of dispersion is 1.15~1.30；
Preferably, the feed postition of chain extender is the DMF solution that chain extender is added dropwise, and a concentration of 0.5-1g/mL, rate of addition is
10mL/min；
Preferably, chain extending reaction carries out under drying nitrogen, and reaction temperature is 65~90 DEG C, and the reaction time is 3~6h；
Preferably, the number-average molecular weight of polyurethane-urea is 1.0 × 105~5.0 × 105, the coefficient of dispersion is 1.20~1.51；
Preferably, the way of purification of polyurethane-urea is that DMF is added into system to be diluted to a concentration of 6~10g/100mL, 8 times of bodies
Accumulated ice ether settles, and 35~45 DEG C of normal-temperature vacuums of obtained solid are dried to constant weight；
Preferably, the mass content of the end dihydroxy-pyridine compound in polyurethane-urea is 10-25%, and the mass content of PEG is
15-45%.
3. the preparation method of polyurethane-urea according to claim 2, it is characterised in that：It holds dihydroxy-pyridine compound and gathers
The molar ratio 6 of ethylene glycol:1~10:1.
4. the preparation method of polyurethane-urea according to claim 2, it is characterised in that：- the NCO of chain extender and end dihydroxy
The molar ratio of-the OH of pyridine compounds and polyethylene glycol summations is 1.01:1~1.05:1.
5. the preparation method of polyurethane-urea according to claim 2, it is characterised in that：The preparation side of polyurethane-urea membrane material
Method is：Obtained pH sensitive polyurethane urea materials are dissolved in organic solvent, the molten of a concentration of 4~7% (g/mL) is made into
Liquid is volatilized into film preparation through solvent and obtains polyurethane film material；
Preferably, solvent volatilization temperature is 15~25 DEG C, and normal pressure 60~90h of volatilization dries by normal-temperature vacuum, obtains polyurethane-urea
Membrane material；
Preferably, the organic solvent is chloroform, dichloromethane, one kind of acetone or dioxane or in which several mixed
Bonding solvent；
Preferably, swellbility of the polyurethane-urea membrane material when medium pH is 1~3 is more than 180%, in neutral or alkaline medium
Swellbility is less than 20%.
6. the preparation method of polyurethane-urea according to claim 2, it is characterised in that：A kind of end dihydroxy-pyridine compound
Preparation method, the specific steps are：
1- thioglycerols are dissolved in anhydrous dimethyl sulfoxide, 4-vinylpridine and catalyst two is added in dry argon gas deoxygenation
Isopropylamine reacts 24-36h at normal temperatures, after reaction, by the molten sedimentation of anhydrous ether of 20~30 times of volumes of mixture,
Filtering, anhydrous ether washing, is finally dried under vacuum to constant weight, yield is about 90-95% at 70-90 DEG C；
Preferably, a concentration of 1.0g/mL of anhydrous dimethyl sulfoxide；
Preferably, catalyst diisopropylamine accounts for the 1~3% of reactant gross mass；
The concrete structure for the end dihydroxy-pyridine compound that the preparation method obtains is：
7. the preparation method of polyurethane-urea according to claim 6, it is characterised in that：1- thioglycerols and 4- vinylpyridines
Pyridine molar ratio is 1.05:1~1.08:1.
8. the preparation method of polyurethane-urea according to claim 2, it is characterised in that：Two isocyanides of the structure containing urea groups
The preparation method of acid esters, the specific steps are：
1) under drying nitrogen protection and mechanical agitation, Putriscine is added drop-wise in L-lysine diisocyanate, at room temperature
After reacting about 1-3h, suspending liquid A is obtained；
2) n-hexane is added into suspending liquid A, after stirring evenly, suction filtration obtains white solid, is washed repeatedly to filter with n-hexane
Liquid IR detections are without-NCO absorption peaks (2270cm-1), it is dried under vacuum to constant weight, obtains white powder diisocyanate；
Preferably, in step 1) L-lysine diisocyanate and Putriscine-NCO:NH2Molar ratio be 6:1~12:
1；
Preferably, the volume of n-hexane is 4 times of suspending liquid A volume in step 2)；
The diisocyanate that the preparation method obtains is that L-lysine diisocyanate -1,4- butanediamine-L-lysine two is different
Cyanate, structural formula are as follows：
9. a kind of pH sensitive biodegradable polyurethane urea is as the application in the carrier of drug.
10. application according to claim 9, it is characterised in that：The polyurethane-urea is prepared as polyurethane-urea medicine carrying membrane material
The medical materials such as material, foamed material, conduit material；
The preparation method of the medicine carrying membrane material is that use can be dissolved with drug in the membrane material preparation process described in claim 5
Organic solvent, medicine carrying membrane material is prepared by the solution evaporation method described in claim 5；
Preferably, vitro drug release amount of the polyurethane-urea membrane material when medium pH is 1~3 is more than 70%, in neutral or alkali
Property medium in vitro drug release amount be less than 10%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217985A (en) * | 2020-03-03 | 2020-06-02 | 方鼎科技有限公司 | Metal coordination self-healing polyurethane elastomer and preparation method thereof |
| CN114907540A (en) * | 2022-05-17 | 2022-08-16 | 浙江欧鹿医疗器械有限公司 | Polyurethane high-molecular polymer and preparation method thereof, polyurethane high-molecular polymer hydrogel, kit and application thereof |
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| US4246263A (en) * | 1979-10-15 | 1981-01-20 | Pfizer Inc. | Antiinflammatory and immunoregulatory pyrimidines, their method of use and pharmaceutical compositions |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217985A (en) * | 2020-03-03 | 2020-06-02 | 方鼎科技有限公司 | Metal coordination self-healing polyurethane elastomer and preparation method thereof |
| CN111217985B (en) * | 2020-03-03 | 2020-11-06 | 方鼎科技有限公司 | Metal coordination self-healing polyurethane elastomer and preparation method thereof |
| CN114907540A (en) * | 2022-05-17 | 2022-08-16 | 浙江欧鹿医疗器械有限公司 | Polyurethane high-molecular polymer and preparation method thereof, polyurethane high-molecular polymer hydrogel, kit and application thereof |
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