CN103980487A - Preparation method for degradable porous polyethylene glycol - Google Patents
Preparation method for degradable porous polyethylene glycol Download PDFInfo
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- CN103980487A CN103980487A CN201410187588.6A CN201410187588A CN103980487A CN 103980487 A CN103980487 A CN 103980487A CN 201410187588 A CN201410187588 A CN 201410187588A CN 103980487 A CN103980487 A CN 103980487A
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- polyoxyethylene glycol
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Abstract
The invention discloses a preparation method for degradable porous polyethylene glycol. The preparation method comprises the following steps: with oxirane as a raw material, synthesizing three-arm polyethylene glycol by using an alkaline ring opening process; preparing a macro-molecular initiator; carrying out ring-opening polymerization with gamma-benzyl-L-glutamate-carboxylic acid anhydride (NCA) so as to obtain a star-block copolymer with PEG as a core and poly(gamma-benzyl-L-glutamate) as an arm; removing a benzyl protective group in poly(gamma-benzyl-L-glutamate) through hydrolysis so as to obtain a star polyethylene glycol/polyglutamic acid block copolymer; and adding low-molecular-weight polyglutamic acid and dissolving the block copolymer with water by using amphipathicity of the block copolymer so as to form a nanometer porous material. The block copolymer has a hexagonal prism-like structure, the continuous phase of the block copolymer is polyethylene glycol, and the material has nanometer holes. The material has nanometer holes, overcomes the disadvantage of poor processability of a traditional linear polyethylene glycol material, exerts no toxic and side effects and can be used as a drug carrier material, a medical implant material and a material for a part of an in-vivo continuous dosing apparatus.
Description
Technical field
The present invention relates to a kind of degradable poly ethylene glycol material, particularly relate to a kind of preparation method with nanometer level microporous block macromolecular material.Belong to polymer chemistry and technical field of polymer.
Background technology
Poly(lactic acid) (Polylactic acid, PLA) be that a new generation of developing rapidly the nineties in 20th century can degradable macromolecular material, it has good biocompatibility, class bio-medical material and environment-friendly materials of food and drug administration (Food and Drug Adiministration, FDA) approval.From the sixties in 20th century, scientific worker starts to pay close attention to the degradation property of poly-lactic acid material, and first using poly-lactic acid material as degradable operation stitching wire material.1966, (the Kricheldorf H. R. such as Kulkarni
chemospherein 2001,43,49-54., propose first: low-molecular-weight PLA can degradation in vivo, and final meta-bolites is CO
2and H
2o, harmless, environmentally safe.Simultaneously, by the research of poly(lactic acid) vivo degradation process is found, the intermediate product lactic acid of degraded is the product of eubolism in body, can not accumulate in vivo, therefore PLA can not produce detrimentally affect to organism after degrading in vivo, has caused thus and has usingd the beginning of this class material as bio-medical material.In recent years, it in medicine sustained and controlled release system, has more and more received the concern of scientists as pharmaceutical carrier.
But common line style poly(lactic acid) (Linear polylactic acid, LPLA) there are some shortcomings, for example its solution and bulk viscosity are higher, degree of crystallinity is large, material fragility is high, thermostability is low and low degradation speed, limited to a certain extent it in the widespread use in the fields such as medical, agricultural and packing, particularly at the application aspect Thermosensitive Material Used for Controlled Releasing of Medicine (Wang L., Dong C. M.
j. Polym. Sci. Part A:Polym. Chem.2006,44 (7), 2226-2236.).Star-like poly(lactic acid) (Star-shaped polylactic acids, SPLA) there is the short and molecular weight advantages of higher of side chain, its solution and bulk viscosity are more much lower than same molecular amount LPLA, mobility and solubility property improve, and its degradation speed is but fast than same molecular amount LPLA, thermostability is higher, is conducive to its processed and applied in the bio-medical materials such as medicament slow release.
No matter although line style or star-like poly-lactic acid material have been widely used in Thermosensitive Material Used for Controlled Releasing of Medicine and tissue engineering material aspect, but the restriction due to himself hydrophobic structure, also part comes with some shortcomings, for example its wetting ability is not good, degradation rate is slower, degradation cycle is difficult to regulation and control, and implant inner posterior quadrant easily adheres to material surface etc.Scientists has been carried out the research of the modification of configuration aspects to PLA material for these problems.In order to increase the wetting ability of PLA, common material modified have polyoxyethylene glycol (Polyethylene glycol, PEG) (Moffatt S., Cristiano R.
j. Int. J. Pharm.2006,317,10-13.), polyvinyl alcohol (Poly vinyl alcohol, PVA), dextran (dextran), chitosan and polypeptide (polypeptide) etc.Because polypeptide (also referred to as polyamino acid) is the biodegradable polymer of a class, have low toxicity, good biocompatibility, biodegradable, easily by body, absorbed and the advantage such as metabolism, Amino Acid Unit structure can be selected, hydrophilicity and hydrophobicity is adjustable, started to be applied in the study on the modification of poly(lactic acid), but only had seldom report.
On the other hand, multiporous biological degradable material is the brand-new material system that development in recent years is got up, and is a kind of material with network structure consisting of mutual perforation or blind hole hole, and the border of hole or surface consist of pillar or flat board.It has regularly arranged and big or small adjustable pore passage structure, relative density is low, specific tenacity is high, porosity and surface-area large, perviousness and excellent adsorption and good biocompatibility, the features such as environmental friendliness, are all with a wide range of applications with fields such as separated, nanomaterial assembly, biological chemistry, molecular recognition and pharmaceutical carriers in bulky molecular catalysis, absorption.By us, to the consulting of documents and materials, also there is no so far that a kind of poly-lactic acid material has that processing characteristics is high simultaneously, a feature such as wetting ability, good biodegradability, nanometer level microporous, high Drug loading capacity.
Summary of the invention
The object of the invention is to set up a kind of preparation method of degradable multiporous polyoxyethylene glycol, this polymer materials has the following advantages: good processability, wetting ability, good biodegradability, nanometer level microporous, high Drug loading capacity.
This polyoxyethylene glycol material is a kind of star-shaped polyethylene glycol/polypeptide segmented copolymer; Take oxyethane as raw material, utilize alkaline process open loop method to synthesize three arm polyoxyethylene glycol; Prepare macromole evocating agent; Carry out ring-opening polymerization with benzyl glutamate carboxylic acid anhydride (NCA) and obtain take the star block copolymer that PEG is arm as core poly benzyl glutamate; By hydrolysis, slough the benzyl protecting group in poly benzyl glutamate, obtain star-shaped polyethylene glycol/polyglutamic acid block copolymer; Add lower molecular weight polyglutamic acid, utilize the amphiphilic water of segmented copolymer to be dissolved, form nanoscale porous material.
The technology of preparing scheme of porous polyoxyethylene glycol material is as follows:
1) star-shaped polyethylene glycol is synthetic
2) macromole evocating agent is synthetic
3) preparation of star block copolymer
4) star block copolymer protective reaction
5) preparation process of polyglycol porous material as shown in Figure 3
By above technical scheme, tool of the present invention has the following advantages: 1) degradable multiporous polyoxyethylene glycol has nano micropore structure capable;
2) degradable multiporous polyoxyethylene glycol has hexagonal columnar structure;
3) degradable multiporous polyoxyethylene glycol has high drug loading amount, and good biocompatibility;
4) degradable multiporous polyoxyethylene glycol has pharmaceutical carrier function and discharges pharmic function, can effectively reduce medicine normal tissue organ toxic side effect.
Accompanying drawing explanation
Fig. 1 is the vesicular structure schematic diagram of this polymer materials;
Fig. 2 is the electron photomicrograph (not deprotection) of this polymer materials;
Fig. 3 is the preparation process schematic diagram of polyglycol porous material.
Embodiment
Provide embodiment below so that the present invention is specifically described; but it is worthy of note that following examples are only used to further illustrate the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that the person skilled in the art in this field makes the present invention according to the invention described above content and adjustment still belong to protection scope of the present invention.
Embodiment 1:
1. prepare star block copolymer
Take oxyethane as raw material; utilize classical subtraction open loop method to synthesize three arms or multi-arm star-shaped polyethylene glycol; existence due to the hydroxyl of polymer ends; can adopt the glycine of amino Boc-radical protection; under the catalysis of DCC/HOBt, react with SPEG and generate SPEG derivative; in trifluoracetic acid/dichloromethane solution, carry out the amino de-Boc protection of above-mentioned product, obtained the star-like macromole evocating agent SPEG-NH of end amido functional group
2.Macromole evocating agent and benzyl glutamate carboxylic acid anhydride (NCA) are carried out to ring-opening polymerization by a certain percentage, the star block copolymer that to obtain take PEG be arm as core poly benzyl glutamate.Finally, adopt HBr, AcOH, trifluoroacetic acid mixed solution that benzyl protecting group is hydrolyzed, finally obtain star-shaped polyethylene glycol/polyglutamic acid block copolymer.
2. the sign of star block copolymer material self-assembled structures and performance
The chemical structure of polymkeric substance and shape characteristic are the bases of the every character of Study Polymer Melts.This problem intends utilizing gel permeation chromatography (GPC), Fourier transform infrared spectroscopy (FTIR) and nucleus magnetic resonance (NMR) method detect chemical structure and the polymerization degree of polymkeric substance, utilize thermogravimetric analyzer (TGA) to study the thermal characteristics of polymkeric substance, the transformation mutually, the liquid crystal behavior that use differential scanning calorimeter (DSC) research segmented copolymer, utilize one dimension, two-dimentional wide-angle x-ray diffraction instrument (WAXD) to determine the phase structure of each segment in segmented copolymer.The star block copolymer proposing in this problem more easily forms micro phase separation structure, can utilize atomic force microscope (AFM) and transmission electron microscope (TEM) to observe star block copolymer at the self-assembled structures of substrate surface, utilize little angle one dimension, two-dimentional x-ray diffractometer (SAXS) to study the micro phase separation structure of star block copolymer.
3. the preparation of porous material
Obtain after required polyoxyethylene glycol/polyglutamic acid star block copolymer, we will observe its body self-assembly behavior, mainly study its micro phase separation structure.Because the body microphase-separated self-assembled structures of segmented copolymer is relevant with the relative proportion that forms component, by the impacts of factor on the phase of micro phase separation structure and size such as content, molecular weight of research block component, we can determine may be applicable segmented copolymer to carry out aftertreatment.Particularly for the segmented copolymer that forms (six sides) column phase or co-continuous double helix phase, when material forms nano pore, and micro phase separation structure is arranged when even, material is higher for the release efficiency of medicine, during as embedded material and the contact area of body fluid increase, be conducive to improve the degradation speed of material.We as the impact on material micro phase separation structure such as solvent species, solvent evaporates speed, make the PGA block in polymkeric substance outside form column or double-spiral structure to obtain top condition research material preparation condition.
The synthetic PEG-b-PGA star block copolymer obtaining in a certain amount of lower molecular weight PGA homopolymer and above-mentioned route is carried out to blend, can obtain the hexagonal columnar phase micro phase separation structure that we need, phase structure can be by confirmations such as low-angle scattering of X-rays and high-resolution electron microscopes.The impact of composition etc. by research blend on the phase of micro phase separation structure and size, we can select suitable blend to carry out aftertreatment.On the other hand, if multipolymer forms co-continuous double helix phase, also may be used as porous material.Then we,, by having the film water treatment of column phase or co-continuous double helix phase structure, dissolve PGA homopolymer, just obtain the modified porous material of star-shaped polyethylene glycol containing hydrophilic nano duct, the carrier of useful as drug model compound.
4. porous star block copolymer is as the research of pharmaceutical carrier
This experiment is intended by existence form and the concentration of steady-state fluorescence spectral characterization and mensuration pyrene, with prove this based block copolymer whether can be in water solution system stable micro-molecular compound, and then discharge in EPC liposome, thereby explore this type of macromolecular material as the potential application of pharmaceutical carrier from the complex body of high-molecular block copolymer-pyrene.Main employing steady-state fluorescence spectroscopic analysis: the spectrum of all samples all records by right angle light path in 4 mL cuvettes.The spectrum of solid-state pyrene crystal is measured by solid support.While doing fluorescence emission spectrum mensuration, emission spectrum wavelength region is 350～650 nm, and excitation wavelength is 336 nm.Excitation spectrum records at emission wavelength 374 nm and 470 nm that represent pyrene monomer and excimer transmitting respectively.All scanning exciting light slits are made as 5 nm, and utilizing emitted light slit is made as 2.5 nm, and PMT voltage is all made as 400 volts, and sweep velocity is 240 nm/min, and spectrum correction is all made as opens to eliminate the wavelength dependency of grating and monitor response.Each Sample Scan is averaged for three times.Be determined at 25
ounder C, carry out.
Finally it should be noted that, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art should understand, can a minute technical scheme for invention be modified or be replaced on an equal basis, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in the middle of claim scope of the present invention.
Claims (7)
1. a degradable multiporous polyoxyethylene glycol, its constitutional features is: described macromolecular material is the star-like type multipolymer being formed by hydrophobicity polyoxyethylene glycol segment and the coupling of wetting ability polyglutamic acid segment.
2. a method of preparing degradable multiporous polyoxyethylene glycol claimed in claim 1 is carried out as follows:
1) take L-rac-Lactide as raw material, utilize stannous octoate catalysis open loop method to synthesize three arm polyoxyethylene glycol;
2) prepare macromole evocating agent;
3) carry out ring-opening polymerization with benzyl glutamate carboxylic acid anhydride and obtain take the star block copolymer that polyoxyethylene glycol is arm as core poly benzyl glutamate;
4) by hydrolysis, slough the benzyl protecting group in poly benzyl glutamate, obtain star-shaped polyethylene glycol/polyglutamic acid block copolymer;
5) add lower molecular weight polyglutamic acid, utilize the amphiphilic water of segmented copolymer to be dissolved, form nanoscale porous material.
3. the preparation method of a kind of degradable multiporous polyoxyethylene glycol according to claim 2, is characterized in that the catalyzer that in aforesaid method, star-type polymer that step 1) is closed is used is stannous octoate.
4. the preparation method of a kind of degradable multiporous polyoxyethylene glycol according to claim 2, is further characterized in that the polymerization single polymerization monomer that in aforesaid method, step 3) is used is benzyl glutamate carboxylic acid anhydride.
5. the preparation method of a kind of degradable multiporous polyoxyethylene glycol according to claim 2, is further characterized in that in the ring-opening polymerization that in aforesaid method, step 3) is carried out and uses primary amine to carry out polyreaction as initiator.
6. a kind of degradable multiporous polyoxyethylene glycol according to claim 2, is further characterized in that: this macromolecular material is the formed porous material of polyoxyethylene glycol and polyglutamic acid.
7. a kind of degradable multiporous polyoxyethylene glycol according to claim 2, is further characterized in that: described porous polymer materials has hexagonal columnar structure clearly.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884917A (en) * | 2016-05-20 | 2016-08-24 | 江南大学 | Straight-chain dextrin-based lipidosome and preparation method thereof |
| CN111808293A (en) * | 2019-04-11 | 2020-10-23 | 九度(上海)化学有限公司 | Polyhydroxy polyester carboxylic acid polymer for preparing solvent type thermal foaming ink |
| CN112263547A (en) * | 2020-11-26 | 2021-01-26 | 深圳大学 | Multifunctional nano-drug carrier, preparation method thereof and drug-loaded composition |
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| CN102911368A (en) * | 2012-11-16 | 2013-02-06 | 苏州大学 | Amphiphilic triblock copolymer with acid sensitivity and preparation method and application thereof |
| CN102942695A (en) * | 2012-12-04 | 2013-02-27 | 中国科学院长春应用化学研究所 | Polymer, glucose nano gel, glucose nano gel composition and preparation method thereof |
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| CN103113579A (en) * | 2013-02-21 | 2013-05-22 | 华东理工大学 | Polyglutamic acid derivative as well as hydrogel and preparation method of polyglutamic acid derivative |
| CN103483582A (en) * | 2013-08-22 | 2014-01-01 | 山东大学 | Biodegradable polymer vesicle with pH responsiveness, and preparation method and application thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105884917A (en) * | 2016-05-20 | 2016-08-24 | 江南大学 | Straight-chain dextrin-based lipidosome and preparation method thereof |
| CN105884917B (en) * | 2016-05-20 | 2018-05-25 | 江南大学 | A kind of linear dextrin base liposome and preparation method thereof |
| CN111808293A (en) * | 2019-04-11 | 2020-10-23 | 九度(上海)化学有限公司 | Polyhydroxy polyester carboxylic acid polymer for preparing solvent type thermal foaming ink |
| CN111808293B (en) * | 2019-04-11 | 2022-04-08 | 九度(上海)化学有限公司 | Polyhydroxy polyester carboxylic acid polymer for preparing solvent type thermal foaming ink |
| CN112263547A (en) * | 2020-11-26 | 2021-01-26 | 深圳大学 | Multifunctional nano-drug carrier, preparation method thereof and drug-loaded composition |
| CN112263547B (en) * | 2020-11-26 | 2022-12-20 | 深圳大学 | Multifunctional nano-drug carrier, preparation method thereof and drug-loaded composition |
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Application publication date: 20140813 |