CN101544748B - Phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer, micelle and preparation method thereof - Google Patents
Phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer, micelle and preparation method thereof Download PDFInfo
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- CN101544748B CN101544748B CN2009100615753A CN200910061575A CN101544748B CN 101544748 B CN101544748 B CN 101544748B CN 2009100615753 A CN2009100615753 A CN 2009100615753A CN 200910061575 A CN200910061575 A CN 200910061575A CN 101544748 B CN101544748 B CN 101544748B
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Abstract
The invention relates to a phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer and a preparation method thereof. Under the microwave irradiation, polyethyleneglycol first undergoes a reaction with a phosphorus acylated agent to form phosphorus acylated polyethyleneglycol and then undergoes a loop opening insertion polymerization reaction with caprolactone to form the amphiphilic polycaprolactone-polyethyleneglycol block copolymer. The block copolymer forms a micelle in water through self assembly. The method not only avoids the use of metal bearing catalyst, but also avoids the residual of a micromolecular catalyst in a polymerization product and improves the in-vivo safety of the polymerization product which is used as biological medical material. The method further avoids the formation of a polycaprolactone homopolymer, thereby not only avoiding the troublesome process of purifying the polymerization product, but also improving the utilization rate of the raw materials and the material performance of the polymerization product. In addition, the method has the advantages of high efficiency and rapidness. The obtained micelle which is taken as a nano carrier has found wide application in the fields of medicine controlled release, targeted administration, genetic treatment, and the like.
Description
Technical field
The present invention relates to a class phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer, microwave preparation and micella, belong to chemical field.
Background technology
Polycaprolactone is as drug delivery carrier, can realize the target of medicine and controlled, thereby improves the utilization ratio of medicine, heightens the effect of a treatment.But the polycaprolactone of surface hydrophobicity is short cycling time in vivo, so need carry out hydrophilic modification to it.Normally cause the caprolactone monomer ring-opening polymerization to form the polycaprolactone-polyethylene glycol amphipathic nature block polymer, be used for aspects such as medicine sustained release, target administration and gene therapy as nano carrier with copolymer micelle with polyoxyethylene glycol.Polycaprolactone-polyethylene glycol is an amphipathic nature block polymer with good biocompatibility and application security, but the resulting segmented copolymer of traditional method has the following disadvantages:
1. unavoidably contain the metal remained catalyzer in the polycaprolactone-polyethylene glycol of the synthetic gained of traditional method (metal catalyst catalysis), influence of the security of this multipolymer as bio-medical material.
2. the polycaprolactone that has homopolymerization in the product with polyoxyethylene glycol initiation caprolactone monomer ring-opening polymerization gained mixes wherein, and removing homopolymer wastes time and energy, and is difficult to eliminate.
Therefore, how avoiding the doping of the polycaprolactone of the residual and homopolymerization of metal catalyst in the polycaprolactone-polyethylene glycol product is a key issue.
Summary of the invention
The object of the present invention is to provide a kind of very convenient fast, do not have residual and adulterated phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer of polycaprolactone homopolymer of metal catalyst and preparation method thereof and micella in the product.This method raw material greenization commercialization, step is easy, has shortened the reaction times, has reduced energy expenditure.
Technical scheme provided by the invention is:
The phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer, its chemical structure meets following general formula:
Wherein, R=methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-or phenyl, PCL=polycaprolactone, PEG=polyoxyethylene glycol.
According to technical scheme of the present invention, molecular weight Mn=500～10000 of described polyoxyethylene glycol.
The present invention also provides the preparation method of above-mentioned phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer: add polyoxyethylene glycol and phosphorous acid dialkyl ester in polymerizing pipe, vacuumize (＜50Pa) tube sealing, place microwave reactor 170-680 watt of reaction 10-60 minute then, obtaining molecular weight is the phosphorus acylated polyoxyethylene glycol of Mn=1000～30000; Phosphorus acylated polyoxyethylene glycol that will obtain again and caprolactone monomer add in another polymerizing pipe; vacuumize (＜50Pa) tube sealing; place microwave reactor; 170-680 watt of reaction 10-60 minute, thereby obtain the phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer that molecular weight is Mn=2000～50000.This segmented copolymer is dissolved in the water and promptly obtains the phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer micelle.
Described phosphorous acid dialkyl ester structure meets following general formula:
Wherein, R=methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-or phenyl.
According to technical scheme of the present invention, used microwave frequency is 2.45GHz.
According to technical scheme of the present invention, in the reaction of synthetic phosphorus acylated polyoxyethylene glycol, the mol ratio of raw materials used polyoxyethylene glycol and phosphorous acid dialkyl ester is 1: 1～10: 1; In phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer preparation feedback, the mass ratio of phosphorus acylated polyoxyethylene glycol and caprolactone is 2: 1～1: 10.
According to technical scheme of the present invention, in the micella preparation process, the mass ratio of phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer and water is 1: 1～1: 100.
By such scheme as can be known, the invention provides a class phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer, microwave preparation and micella.Compare with traditional method, do not have the residual and polycaprolactone homopolymer doping of metal catalyst in the segmented copolymer that present method directly makes, and, simple to operate, adopt microwave heating, shortened the reaction times, reduced energy expenditure.The inventive method has not only avoided using any metallic catalyzer, but also has avoided micromolecule catalyst residual in polymerisate, has improved polymerisate as security in the body of bio-medical material.This method has also been avoided the formation of polycaprolactone homopolymer, has not only avoided the complicated processes of purifying polymerisate but also improved the rate of utilization of raw material and the material property of polymerisate.This method also has efficiently advantage fast simultaneously.The prepared micella of this method has extensive use as nano-carrier in fields such as medicine sustained release, target administration and gene therapies.
The experiment proved that; adopt method provided by the invention can obtain not having the residual and polycaprolactone homopolymer miscellaneous phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer micelle of metal catalyst easily, this micella can substitute conventional polycaprolactone-polyethylene glycol block copolymer micella as the drug sustained release system solid support material.
Description of drawings
Fig. 1 is the phosphorus acylated polyoxyethylene glycol of embodiments of the invention 1 gained (Fig. 1-a) and phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer (the gel permeation chromatography figure of Fig. 1-b).
Fig. 2 is that (Fig. 2-a) and phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer be (Fig. 2's-b) for the phosphorus acylated polyoxyethylene glycol of embodiments of the invention 1 gained
31The P nuclear magnetic spectrogram.
The transmission electron microscope picture of Fig. 3 embodiments of the invention 1 gained phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer micelle.
Fig. 4 is the micelle-forming concentration figure of embodiments of the invention 1 gained phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer micelle.
Fig. 5 is the release-time diagram of embodiments of the invention 1 gained phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer micelle.
Embodiment
The present invention will be further described below in conjunction with embodiment and accompanying drawing.
Embodiment 1: in the glass polymerizing pipe, add the mixture that 1.0254 gram polyoxyethylene glycol [number-average molecular weight (down with) 2000] and 0.0280 restrain diisopropyl phosphite (mol ratio 3: 1), with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Polymerizing pipe with sealing places microwave reactor then, and microwave frequency is 2.45GHz, and power is 340 watts of startup microwave reactors and reacted 30 minutes.0.2600 gram products therefrom and 1.0011 being restrained oneself joins in another glass polymerizing pipe after lactone (mass ratio 1: 4) mixes again, with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Equally, the polymerizing pipe that seals is placed microwave reactor, microwave frequency is 2.45GHz, and power is 340 watts of startup microwave reactors and reacted 30 minutes.At last, products therefrom is dissolved in the water (product is 1: 40 with the quality ratio) promptly obtain the polycaprolactone-polyethylene glycol block copolymer micella.Polycaprolactone-polyethylene glycol block copolymer molecular weight Mn=7500.
By Fig. 1-a and Fig. 2-b as can be seen, the reaction of diisopropyl phosphite and Macrogol 2000 has obtained phosphorus acylated polyoxyethylene glycol; By Fig. 1-b as can be seen, phosphorus acylated polyoxyethylene glycol and caprolactone monomer reaction products therefrom molecular weight is higher than Macrogol 2000 and phosphorus acylated polyoxyethylene glycol.Fig. 2, phosphorus acylated polyoxyethylene glycol (Fig. 2-a) and reaction gained final product (Fig. 2-b)
31The P nuclear magnetic spectrogram illustrates that the gained final product is a phosphorus acylated polycaprolactone.In conjunction with transmission electron microscope picture (Fig. 3) and micelle-forming concentration figure (Fig. 4, micelle-forming concentration CMC=24.83 milligram), prove that the gained final product is an amphipathic nature block polymer, i.e. the phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer.
Embodiment 2: in the glass polymerizing pipe, add the mixture that 1.0379 gram polyoxyethylene glycol (500) and 0.0230 restrain dimethylphosphite (mol ratio 10: 1), with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Polymerizing pipe with sealing places microwave reactor then, and microwave frequency is 2.45GHz, and power is 170 watts of startup microwave reactors and reacted 60 minutes.0.9827 gram products therefrom and 0.4983 being restrained oneself joins in another glass polymerizing pipe after lactone (mass ratio 2: 1) mixes again, with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Equally, the polymerizing pipe that seals is placed microwave reactor, microwave frequency is 2.45GHz, and power is 170 watts of startup microwave reactors and reacted 60 minutes.At last, products therefrom is dissolved in the water (product is 1: 1 with the quality ratio) promptly obtain the polycaprolactone-polyethylene glycol block copolymer micella.Gained polycaprolactone-polyethylene glycol block copolymer micellar micelle-forming concentration CMC=29.62 milligram.Polycaprolactone-polyethylene glycol block copolymer molecular weight Mn=2140.
Embodiment 3: in the glass polymerizing pipe, add the mixture that 1.0582 gram polyoxyethylene glycol (10000) and 0.0148 restrain diethyl phosphite (mol ratio 1: 1), with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Polymerizing pipe with sealing places microwave reactor then, and microwave frequency is 2.45GHz, and power is 680 watts of startup microwave reactors and reacted 10 minutes.0.1183 gram products therefrom and 1.1028 being restrained oneself joins in another glass polymerizing pipe after lactone (mass ratio 1: 10) mixes again, with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Equally, the polymerizing pipe that seals is placed microwave reactor, microwave frequency is 2.45GHz, and power is 680 watts of startup microwave reactors and reacted 30 minutes.At last, products therefrom is dissolved in the water (product is 1: 100 with the quality ratio) promptly obtain the polycaprolactone-polyethylene glycol block copolymer micella.Gained polycaprolactone-polyethylene glycol block copolymer micellar micelle-forming concentration CMC=35.78 milligram.Polycaprolactone-polyethylene glycol block copolymer molecular weight Mn=48950.
Embodiment 4: in the glass polymerizing pipe, add the mixture that 1.0282 gram polyoxyethylene glycol (4000) and 0.0218 restrain phosphorous acid dipropyl (mol ratio 2: 1), with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Polymerizing pipe with sealing places microwave reactor then, and microwave frequency is 2.45GHz, and power is 510 watts of startup microwave reactors and reacted 20 minutes.0.3521 gram products therefrom and 1.0632 being restrained oneself joins in another glass polymerizing pipe after lactone (mass ratio 1: 3) mixes again, with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Equally, the polymerizing pipe that seals is placed microwave reactor, microwave frequency is 2.45GHz, and power is 425 watts of startup microwave reactors and reacted 40 minutes.At last, products therefrom is dissolved in the water (product is 1: 80 with the quality ratio) promptly obtain the polycaprolactone-polyethylene glycol block copolymer micella.Gained polycaprolactone-polyethylene glycol block copolymer micellar micelle-forming concentration CMC=42.61 milligram.Polycaprolactone-polyethylene glycol block copolymer molecular weight Mn=15210.
Embodiment 5: in the glass polymerizing pipe, add the mixture that 1.0134 gram polyoxyethylene glycol (6000) and 0.0082 restrain di-n-butyl phosphite (mol ratio 4: 1), with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Polymerizing pipe with sealing places microwave reactor then, and microwave frequency is 2.45GHz, and power is 680 watts of startup microwave reactors and reacted 20 minutes.0.2051 gram products therefrom and 1.0262 being restrained oneself joins in another glass polymerizing pipe after lactone (mass ratio 1: 5) mixes again, with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Equally, the polymerizing pipe that seals is placed microwave reactor, microwave frequency is 2.45GHz, and power is 340 watts of startup microwave reactors and reacted 50 minutes.At last, products therefrom is dissolved in the water (product is 1: 90 with the quality ratio) promptly obtain the polycaprolactone-polyethylene glycol block copolymer micella.Gained polycaprolactone-polyethylene glycol block copolymer micellar micelle-forming concentration CMC=22.03 milligram.Polycaprolactone-polyethylene glycol block copolymer molecular weight Mn=18360.
Embodiment 6: in the glass polymerizing pipe, add the mixture that 1.0466 gram polyoxyethylene glycol (8000) and 0.0128 restrain phosphorous acid diisobutyl ester (mol ratio 2: 1), with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Polymerizing pipe with sealing places microwave reactor then, and microwave frequency is 2.45GHz, and power is 680 watts of startup microwave reactors and reacted 40 minutes.0.1285 gram products therefrom and 1.032 being restrained oneself joins in another glass polymerizing pipe after lactone (mass ratio 1: 8) mixes again, with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Equally, the polymerizing pipe that seals is placed microwave reactor, microwave frequency is 2.45GHz, and power is 510 watts of startup microwave reactors and reacted 50 minutes.At last, products therefrom is dissolved in the water (product is 1: 70 with the quality ratio) promptly obtain the polycaprolactone-polyethylene glycol block copolymer micella.Gained polycaprolactone-polyethylene glycol block copolymer micellar micelle-forming concentration CMC=32.16 milligram.Polycaprolactone-polyethylene glycol block copolymer molecular weight Mn=26850.
Embodiment 7: in the glass polymerizing pipe, add the mixture that 1.0158 gram polyoxyethylene glycol (1000) and 0.0395 restrain phosphorous acid diphenyl ester (mol ratio 6: 1), with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Polymerizing pipe with sealing places microwave reactor then, and microwave frequency is 2.45GHz, and power is 255 watts of startup microwave reactors and reacted 40 minutes.0.5023 gram products therefrom and 1.0254 being restrained oneself joins in another glass polymerizing pipe after lactone (mass ratio 1: 2) mixes again, with oil pump vacuumize (＜50Pa), applying argon gas, tube sealing after three times repeatedly.Equally, the polymerizing pipe that seals is placed microwave reactor, microwave frequency is 2.45GHz, and power is 340 watts of startup microwave reactors and reacted 40 minutes.At last, products therefrom is dissolved in the water (product is 1: 100 with the quality ratio) promptly obtain the polycaprolactone-polyethylene glycol block copolymer micella.Gained polycaprolactone-polyethylene glycol block copolymer micellar micelle-forming concentration CMC=27.23 milligram.Polycaprolactone-polyethylene glycol block copolymer molecular weight Mn=4700.
Embodiment 8: with 0.4 gram embodiment 1 gained phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer and 30 milligrams of Prednisone acetate mixed dissolutions in 10 milliliters of N; dinethylformamide; dialysis is until N in 1000 ml waters; dinethylformamide removes fully; obtain being enclosed with the phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer micelle of Prednisone acetate, measure its release-time curve (Fig. 5).
As shown in Figure 5, the release time length of this carrier micelle can reach 350 hours, in addition smaller particle size (40 ± 5 nanometer) (Fig. 3), be a class excellent property the slow releasing carrier of medication material.
Claims (8)
1. phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer, its chemical structure meets following general formula:
Wherein, R=methyl, ethyl, sec.-propyl, normal-butyl, isobutyl-or phenyl, PCL=polycaprolactone, PEG=polyoxyethylene glycol.
2. segmented copolymer according to claim 1 is characterized in that: the molecular weight of described polyoxyethylene glycol is Mn=500～10000.
3. the preparation method of claim 1 or 2 described phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymers, it is characterized in that: in polymerizing pipe, add polyoxyethylene glycol and phosphorous acid dialkyl ester, vacuumize tube sealing, place microwave reactor 170-680 watt of reaction 10-60 minute then, obtaining molecular weight is the phosphorus acylated polyoxyethylene glycol of Mn=1000～30000; Phosphorus acylated polyoxyethylene glycol that will obtain again and caprolactone monomer add in another polymerizing pipe; vacuumize tube sealing; place microwave reactor,, thereby obtain the phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer that molecular weight is Mn=2000～50000 170-680 watt of reaction 10-60 minute.
4. preparation method according to claim 3 is characterized in that: described phosphorous acid dialkyl ester structure meets following general formula:
Wherein, R=methyl, ethyl, sec.-propyl, normal-butyl, isobutyl-or phenyl.
5. according to claim 3 or 4 described preparation methods, it is characterized in that: the mol ratio of polyoxyethylene glycol and phosphorous acid dialkyl ester is 1: 1～10: 1; The phosphorus acylated polyoxyethylene glycol and the mass ratio of caprolactone are 2: 1～1: 10.
6. according to claim 3 or 4 described preparation methods, it is characterized in that: used microwave frequency is 2.45GHz.
7. phosphorus acylated polycaprolactone-polyethyleneglycol block copolymer micelle, it is characterized in that: being dissolved in the water by claim 1 or 2 described phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer blocks obtains.
8. according to the described block copolymer micelle of claim 7, it is characterized in that: the mass ratio of phosphorus acylated polycaprolactone-polyethyleneglycol segmented copolymer and water is 1: 1～1: 100.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1154708A (en) * | 1994-06-13 | 1997-07-16 | 曾尼卡有限公司 | Polyether phosphates |
| CN1978492A (en) * | 2006-11-24 | 2007-06-13 | 南京大学 | Polycaprolactone-polyethylene glycol block copolymer, and its preparing method and use |
| CN101474408A (en) * | 2008-01-02 | 2009-07-08 | 中国科学技术大学 | Polyethylene glycol monomethyl ether-polycaprolactone-polyphosphate triblock copolymer and siRNA medicament carrier prepared thereby |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1154708A (en) * | 1994-06-13 | 1997-07-16 | 曾尼卡有限公司 | Polyether phosphates |
| CN1978492A (en) * | 2006-11-24 | 2007-06-13 | 南京大学 | Polycaprolactone-polyethylene glycol block copolymer, and its preparing method and use |
| CN101474408A (en) * | 2008-01-02 | 2009-07-08 | 中国科学技术大学 | Polyethylene glycol monomethyl ether-polycaprolactone-polyphosphate triblock copolymer and siRNA medicament carrier prepared thereby |
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