CN105949455A - Preparation method of polyethylene glycol hydrogel - Google Patents
Preparation method of polyethylene glycol hydrogel Download PDFInfo
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- CN105949455A CN105949455A CN201610306233.3A CN201610306233A CN105949455A CN 105949455 A CN105949455 A CN 105949455A CN 201610306233 A CN201610306233 A CN 201610306233A CN 105949455 A CN105949455 A CN 105949455A
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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
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
- C08G65/48—Polymers modified by chemical after-treatment
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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
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2371/08—Polyethers derived from hydroxy compounds or from their metallic derivatives
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2387/00—Characterised by the use of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds
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Abstract
The invention discloses a preparation method of polyethylene glycol hydrogel and belongs to the technical field of hydrogel. According to the method, polyethylene glycol is taken as a raw material and is subjected to esterification with cysteine, multi-mercapto linear polyethylene glycol ester is produced, multi-mercapto linear polyethylene glycol ester and citric anhydride are subjected to condensation polymerization under the catalysis of trifluoromethane sulfonic acid rare earth to produce multi-double-bond linear polyethylene glycol type polyether ester, then, multi-mercapto linear polyethylene glycol ester and multi-double-bond linear polyethylene glycol type polyether ester are mixed and subjected to an addition reaction through mercapto-double bond Michael, hydrogel is prepared, glycosidase and esterase are added at the low temperature, the mixture is stored at the low temperature, the activity of enzymes is inhibited at the low temperature, enzymes are in high activity at the temperature of a human body after hydrogel enters the human body, hydrogel is hydrolyzed, molecules which can be absorbed or degraded by the human body are produced, and degradation of hydrogel is accelerated due to addition of the enzymes. The method is simple to operate and easy to industrialize.
Description
Technical field
The invention discloses the preparation method of a kind of polyethylene glycol type hydrogel, belong to technical field of hydrogel.
Background technology
Realize a kind of method that the medicine control release at human lesion position is preferable treatment disease.Medicine embeds or is bonded on macromolecule carrier to realize the control release of medicine.Main macromolecule carrier has macromolecule micelle, medicine/macromolecule conjugated body, gel etc..Phase late 1950s, using the macromolecular material such as silicone rubber, poly-(vinylacetate) as the carrier of small-molecule drug, it is achieved that the continued smooth release of medicine.But these macromolecular material non-degradables, after drug release completes, need to remove these these carriers by the method for operation, add the misery of patient.Subsequently, develop the seventies using poly-(lactide, lactide) degradable high polymer material as representative as pharmaceutical carrier, and developed luteinizing hormone releasing hormone/PLGA microsphere and be used for treating endometriosis, obtain FDA Food and Drug Administration (FDA) approval, it is applied in clinic, its single administration, can maintain curative effect nearly about one month.But the same problem in the face of needing just pharmaceutical carrier to be implanted human body by operation of this kind of material.Injection aquagel material can form complicated shape because of its uniqueness without patient is carried out operative treatment in injury, and the strong advantage sticked on when injected organism tissue, as the study hotspot become history decades on drug carrier system and embedded material.Hydrogel refers to that hydrophilic or water miscible macromolecule is cross-linked into the polymeric material having tridimensional network, remaining to keep definite shape after absorbing water by method physically or chemically.In recent years, there is scholar to be prepared for PLAG-PEG-PLGA triblock polymer, achieve sol-gel transition by this polymer temperature-induced, it is achieved that the in-situ injection molding of hydrogel；But this hydrogel is obtained by physical method (such as hydrogen bond, ionic bond, hydrophobic interaction) crosslinking, and mechanical strength is low.The hydrogel obtained by chemical bond crosslinking typically requires cross-linking agent, catalyst etc., the method such as " click chemistry ", light-initiated radical polymerization is utilized to be prepared for hydrogel if any scholar, but need to use metallic catalyst, ultraviolet light, initiator etc. in preparation process, human body can be caused extra injury by this, and reaction condition is bigger with Human Physiology condition difference, have by-product during gelation reaction to generate, it is difficult to use as injectable gel.Therefore study and under the conditions of Human Physiology, be formed in situ injectable aquogel system do not only have the not biggest scientific meaning and have the application prospect of reality.
Polyethylene Glycol (PEG) is the water soluble polymer with good biocompatibility by FDA Food and Drug Administration (FDA) certification, has been widely used in biomedicine field.The Polyethylene Glycol of commercialization has various different molecular weight, and strand two ends can be different groups, can carry out multiple chemical modification, and as acrylic acid reaction can make end group become double bond, double bond can carry out Raolical polymerizable；End group can be made to become alkynyl with propargyl bromide reaction, end alkynyl radical can occur " click-reaction " with nitrine；Atom Transfer Radical Polymerization (ATRP) initiator can be transformed into bromo isobutyryl bromine reaction, carry out " activity/controlled " radical polymerization, be therefore widely used in the preparation of hydrogel.There is scholar to report and the terminal hydroxy group of star Polyethylene Glycol is modified to sulfydryl and double bond, utilize Michael additive reaction to prepare injection aquagel but the synthesis condition harshness of star Polyethylene Glycol is difficult to industrialization, expensive, and need further chemical modification.
Summary of the invention
nullThe technical problem that present invention mainly solves: the synthesis condition harshness for current Polyethylene Glycol is difficult to industrialization，Expensive，And need further chemical modification，And nondegradable problem，Provide the preparation method of a kind of polyethylene glycol type hydrogel，The present invention is with Polyethylene Glycol as raw material，By becoming many sulfydryls linear polyethylene glycol ester with cysteine ester metaplasia，Generate many double bonds linear polyethylene glycol type polyether ester with Citric anhydride polycondensation under trifluoromethane sulfonic acid rare earth catalyst then both to be mixed through sulfydryl-double bond Michael additive reaction at prepared hydrogel，Add glycosidase and esterase at low temperatures，And cryopreservation，The activity of low temperature inhibitory enzyme，After making hydrogel enter human body，When human body temperature, enzyme produces high activity，Hydrogel is made to hydrolyze，Generation can be absorbed by the body or degradable molecule，The degraded adding acceleration hydrogel of enzyme，And the present invention is simple to operate，It is easily achieved industrialization.
In order to solve above-mentioned technical problem, the technical solution adopted in the present invention is:
(1) weigh 10～20g Polyethylene Glycol respectively and 10～20g cysteine join in the 500mL there-necked flask filling 200～300mL deionized waters, 5～10mL0.1mol/LNaOH are added in beaker, temperature controlled water baths is 55～65 DEG C, stirring reaction 3～5h, obtain many sulfydryls linear polyethylene glycol type ester, standby；
(2) weigh 10～20g Polyethylene Glycol respectively and 10～20g Citric anhydrides join in the 1000mL there-necked flask filling 200～300mL deionized waters, it is passed through nitrogen with the speed of 1～2L/min in flask, in beaker, add 0.1～0.2g trifluoromethane sulfonic acid rare earth simultaneously, temperature controlled water baths is 55～65 DEG C, stirring reaction 3～5h, obtains many double bonds linear polyethylene glycol type polyether ester；
(3) many sulfydryls linear polyethylene glycol type polyether ester standby for above-mentioned steps (1) is joined in above-mentioned many double bonds linear polyethylene glycol type polyether ester, with 180～200W ultrasonic echographies 20～30min, obtain dispersion liquid, adding 100～200mLpH in dispersion liquid is the citrate buffer solution of 7.2～7.4, temperature controlled water baths is at 36～38 DEG C, stirring 4～6h, obtains polyethylene glycol type hydrogel emulsion；
(4) above-mentioned hydrogel emulsion is filtered, obtain gel, gel is washed with deionized 3～5 times, then gel is joined in 100～200mL deionized waters, stir 20～30min, obtain polyethylene glycol type hydrogel emulsion；
(5) being sequentially added into 0.2～0.3g glycosidase, 0.2～0.3g esterase in above-mentioned hydrogel, temperature controlled water baths, at 10～15 DEG C, stirs 2～3h, obtains polyethylene glycol type hydrogel, in 10～15 DEG C of cryopreservation.
The method of the application of the present invention: weigh polyethylene glycol type hydrogel that the 1～3g present invention prepares respectively and 0.1～0.3g riboflavin is mixed to get injectable type polyethylene glycol type hydrogel, polyethylene glycol type hydrogel is expelled to the disease sites of skin, inject 2～3 every day, inject 5～7 days, can fully recover.
The invention has the beneficial effects as follows:
(1) present invention utilizes glycosidase and esterase, and cryopreservation, the activity of low temperature inhibitory enzyme, after making hydrogel enter human body, when human body temperature, enzyme produces high activity, makes hydrogel hydrolyze, generation can be absorbed by the body or degradable molecule, the degraded adding acceleration hydrogel of enzyme；
(2) present invention is simple to operate, it is easy to accomplish industrialization.
Detailed description of the invention
Weigh 10～20g Polyethylene Glycol the most respectively and 10～20g cysteine join in the 500mL there-necked flask filling 200～300mL deionized waters, 5～10mL0.1mol/LNaOH are added in beaker, temperature controlled water baths is 55～65 DEG C, stirring reaction 3～5h, obtain many sulfydryls linear polyethylene glycol type ester, standby；Weigh 10～20g Polyethylene Glycol respectively and 10～20g Citric anhydrides join in the 1000mL there-necked flask filling 200～300mL deionized waters, it is passed through nitrogen with the speed of 1～2L/min in flask, in beaker, add 0.1～0.2g trifluoromethane sulfonic acid rare earth simultaneously, temperature controlled water baths is 55～65 DEG C, stirring reaction 3～5h, obtains many double bonds linear polyethylene glycol type polyether ester；Above-mentioned standby many sulfydryls linear polyethylene glycol type polyether ester is joined in above-mentioned many double bonds linear polyethylene glycol type polyether ester, with 180～200W ultrasonic echographies 20～30min, obtain dispersion liquid, adding 100～200mLpH in dispersion liquid is the citrate buffer solution of 7.2～7.4, temperature controlled water baths is at 36～38 DEG C, stirring 4～6h, obtains polyethylene glycol type hydrogel emulsion；Above-mentioned hydrogel emulsion is filtered, obtains gel, gel is washed with deionized 3～5 times, then gel is joined in 100～200mL deionized waters, stir 20～30min, obtain polyethylene glycol type hydrogel emulsion；Being sequentially added into 0.2～0.3g glycosidase, 0.2～0.3g esterase in above-mentioned hydrogel, temperature controlled water baths, at 10～15 DEG C, stirs 2～3h, obtains polyethylene glycol type hydrogel, in 10～15 DEG C of cryopreservation.
Example 1
Weigh 10g Polyethylene Glycol the most respectively and 10g cysteine joins in the 500mL there-necked flask filling 200mL deionized water, adding 5mL0.1mol/LNaOH in beaker, temperature controlled water baths is 55 DEG C, stirring reaction 3h, obtain many sulfydryls linear polyethylene glycol type ester, standby；Weigh 10g Polyethylene Glycol respectively and 10g Citric anhydride joins in the 1000mL there-necked flask filling 200mL deionized water, in flask, the speed with 1L/min is passed through nitrogen, in beaker, add 0.1g trifluoromethane sulfonic acid rare earth simultaneously, temperature controlled water baths is 55 DEG C, stirring reaction 3h, obtains many double bonds linear polyethylene glycol type polyether ester；Above-mentioned standby many sulfydryls linear polyethylene glycol type polyether ester is joined in above-mentioned many double bonds linear polyethylene glycol type polyether ester, with 180W ultrasonic echography 20min, obtain dispersion liquid, adding 100mLpH in dispersion liquid is the citrate buffer solution of 7.2, temperature controlled water baths is at 36 DEG C, stirring 4h, obtain polyethylene glycol type hydrogel emulsion above-mentioned hydrogel emulsion to be filtered, obtain gel, gel is washed with deionized 3 times, then gel is joined in 100mL deionized water, stir 20min, obtain polyethylene glycol type hydrogel emulsion；Being sequentially added into 0.2g glycosidase, 0.2g esterase in above-mentioned hydrogel, temperature controlled water baths, at 10 DEG C, stirs 2h, obtains polyethylene glycol type hydrogel, in 10 DEG C of cryopreservation.
Weigh the polyethylene glycol type hydrogel that the 1g present invention prepares respectively and be mixed to get injectable type polyethylene glycol type hydrogel with 0.1g riboflavin, polyethylene glycol type hydrogel is expelled to the disease sites of skin, injects every day 2 times, inject 7 days, can fully recover；The present invention utilizes glycosidase and esterase, and cryopreservation, the activity of low temperature inhibitory enzyme, after making hydrogel enter human body, when human body temperature, enzyme produces high activity, makes hydrogel hydrolyze, generation can be absorbed by the body or degradable molecule, the degraded adding acceleration hydrogel of enzyme；The present invention is simple to operate, it is easy to accomplish industrialization.
Example 2
Weigh 15g Polyethylene Glycol the most respectively and 15g cysteine joins in the 500mL there-necked flask filling 250mL deionized water, adding 8mL0.1mol/LNaOH in beaker, temperature controlled water baths is 60 DEG C, stirring reaction 4h, obtain many sulfydryls linear polyethylene glycol type ester, standby；Weigh 15g Polyethylene Glycol respectively and 15g Citric anhydride joins in the 1000mL there-necked flask filling 250mL deionized water, in flask, the speed with 1.5L/min is passed through nitrogen, in beaker, add 0.15g trifluoromethane sulfonic acid rare earth simultaneously, temperature controlled water baths is 60 DEG C, stirring reaction 4h, obtains many double bonds linear polyethylene glycol type polyether ester；Above-mentioned standby many sulfydryls linear polyethylene glycol type polyether ester is joined in above-mentioned many double bonds linear polyethylene glycol type polyether ester, with 180～200W ultrasonic echography 25min, obtain dispersion liquid, adding 150mLpH in dispersion liquid is the citrate buffer solution of 7.3, temperature controlled water baths is at 37 DEG C, stirring 5h, obtains polyethylene glycol type hydrogel emulsion；Above-mentioned hydrogel emulsion is filtered, obtains gel, gel is washed with deionized 4 times, then gel is joined in 150mL deionized water, stir 25min, obtain polyethylene glycol type hydrogel emulsion；Being sequentially added into 0.25g glycosidase, 0.25g esterase in above-mentioned hydrogel, temperature controlled water baths, at 13 DEG C, stirs 2.5h, obtains polyethylene glycol type hydrogel, in 13 DEG C of cryopreservation.
Weigh the polyethylene glycol type hydrogel that the 2g present invention prepares respectively and be mixed to get injectable type polyethylene glycol type hydrogel with 0.2g riboflavin, polyethylene glycol type hydrogel is expelled to the disease sites of skin, injects every day 23 times, inject 6 days, can fully recover；The present invention utilizes glycosidase and esterase, and cryopreservation, the activity of low temperature inhibitory enzyme, after making hydrogel enter human body, when human body temperature, enzyme produces high activity, makes hydrogel hydrolyze, generation can be absorbed by the body or degradable molecule, the degraded adding acceleration hydrogel of enzyme；The present invention is simple to operate, it is easy to accomplish industrialization.
Example 3
Weigh 20g Polyethylene Glycol the most respectively and 20g cysteine joins in the 500mL there-necked flask filling 300mL deionized water, adding 10mL0.1mol/LNaOH in beaker, temperature controlled water baths is 65 DEG C, stirring reaction 5h, obtain many sulfydryls linear polyethylene glycol type ester, standby；Weigh 20g Polyethylene Glycol respectively and 20g Citric anhydride joins in the 1000mL there-necked flask filling 300mL deionized water, in flask, the speed with 2L/min is passed through nitrogen, in beaker, add 0.2g trifluoromethane sulfonic acid rare earth simultaneously, temperature controlled water baths is 65 DEG C, stirring reaction 5h, obtains many double bonds linear polyethylene glycol type polyether ester；Above-mentioned standby many sulfydryls linear polyethylene glycol type polyether ester is joined in above-mentioned many double bonds linear polyethylene glycol type polyether ester, with 200W ultrasonic echography 30min, obtain dispersion liquid, adding 200mLpH in dispersion liquid is the citrate buffer solution of 7.4, temperature controlled water baths is at 38 DEG C, stirring 6h, obtains polyethylene glycol type hydrogel emulsion；Above-mentioned hydrogel emulsion is filtered, obtains gel, gel is washed with deionized 5 times, then gel is joined in 200mL deionized water, stir 30min, obtain polyethylene glycol type hydrogel emulsion；Being sequentially added into 0.3g glycosidase, 0.3g esterase in above-mentioned hydrogel, temperature controlled water baths, at 15 DEG C, stirs 3h, obtains polyethylene glycol type hydrogel, in 15 DEG C of cryopreservation.
Weigh the polyethylene glycol type hydrogel that the 3g present invention prepares respectively and be mixed to get injectable type polyethylene glycol type hydrogel with 0.3g riboflavin, polyethylene glycol type hydrogel is expelled to the disease sites of skin, injects every day 3 times, inject 5 days, can fully recover；The present invention utilizes glycosidase and esterase, and cryopreservation, the activity of low temperature inhibitory enzyme, after making hydrogel enter human body, when human body temperature, enzyme produces high activity, makes hydrogel hydrolyze, generation can be absorbed by the body or degradable molecule, the degraded adding acceleration hydrogel of enzyme；The present invention is simple to operate, it is easy to accomplish industrialization.
Claims (1)
1. the preparation method of a polyethylene glycol type hydrogel, it is characterised in that concrete preparation process is:
(1) weigh 10～20g Polyethylene Glycol respectively and 10～20g cysteine join in the 500mL there-necked flask filling 200～300mL deionized waters, 5～10mL0.1mol/LNaOH are added in beaker, temperature controlled water baths is 55～65 DEG C, stirring reaction 3～5h, obtain many sulfydryls linear polyethylene glycol type ester, standby；
(2) weigh 10～20g Polyethylene Glycol respectively and 10～20g Citric anhydrides join in the 1000mL there-necked flask filling 200～300mL deionized waters, it is passed through nitrogen with the speed of 1～2L/min in flask, in beaker, add 0.1～0.2g trifluoromethane sulfonic acid rare earth simultaneously, temperature controlled water baths is 55～65 DEG C, stirring reaction 3～5h, obtains many double bonds linear polyethylene glycol type polyether ester；
(3) many sulfydryls linear polyethylene glycol type polyether ester standby for above-mentioned steps (1) is joined in above-mentioned many double bonds linear polyethylene glycol type polyether ester, with 180～200W ultrasonic echographies 20～30min, obtain dispersion liquid, adding 100～200mLpH in dispersion liquid is the citrate buffer solution of 7.2～7.4, temperature controlled water baths is at 36～38 DEG C, stirring 4～6h, obtains polyethylene glycol type hydrogel emulsion；
(4) above-mentioned hydrogel emulsion is filtered, obtain gel, gel is washed with deionized 3～5 times, then gel is joined in 100～200mL deionized waters, stir 20～30min, obtain polyethylene glycol type hydrogel emulsion；
(5) being sequentially added into 0.2～0.3g glycosidase, 0.2～0.3g esterase in above-mentioned hydrogel, temperature controlled water baths, at 10～15 DEG C, stirs 2～3h, obtains polyethylene glycol type hydrogel, in 10～15 DEG C of cryopreservation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107286093A (en) * | 2017-08-17 | 2017-10-24 | 北京朗依制药有限公司 | The preparation method of 6 chloromethyl morphanthridines |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107286093A (en) * | 2017-08-17 | 2017-10-24 | 北京朗依制药有限公司 | The preparation method of 6 chloromethyl morphanthridines |
| CN107286093B (en) * | 2017-08-17 | 2018-03-06 | 北京朗依制药有限公司 | The preparation method of 6 chloromethyl morphanthridines |
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