CN105061664A - PH and temperature dual responsive copolymer and preparation method and application thereof - Google Patents
PH and temperature dual responsive copolymer and preparation method and application thereof Download PDFInfo
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- CN105061664A CN105061664A CN201510582778.2A CN201510582778A CN105061664A CN 105061664 A CN105061664 A CN 105061664A CN 201510582778 A CN201510582778 A CN 201510582778A CN 105061664 A CN105061664 A CN 105061664A
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Abstract
The invention relates to a pH and temperature dual responsive copolymer and a preparation method and an application thereof, which belong to the technical field of pharmaceutical polymers. A molecular structure of the copolymer is shown as follows, and the molecular weight is 10000 to 30000. The copolymer is prepared in the following steps of (a) preparing a copolymer of diethyl allylmalonate and N-vinylcaprolactam; (b) preparing a copolymer of allylmalonic acid and N-vinylcaprolactam. The copolymer is used for self assembly in water to form nanomicelles as controlled release carriers of podophyllotoxin drugs. Raw materials are low in price and are easy to obtain, a synthetic method is simple, products are easy to separate and purify, and the operability is strong. The copolymer can be assembled by self in a water solution to form stable spherical nanomicelles which have high drug loading capacity and encapsulation efficiency on podophyllotoxin and have pH and temperature dual responsive controlled release performance on the podophyllotoxin, and the copolymer can be used for constructing an intelligent drug controlled release system.
Description
Technical field
The invention belongs to pharmaceutical polymers technical field, be specifically related to the pH that is made up of allyl malonic acid and N-caprolactam and temperature dual response polymer, Preparation Method And The Use.
Background technology
The drug delivery system being carrier with environment-responsive polymkeric substance can respond the small stimulation of external environment and cause the change of self structure, discharge medicine, treatment for numerous disease (as tumour etc.) has the advantages such as long-acting low toxicity, controlled and high drug load, has broad application prospects at biomedical sector.Wherein, comparatively easily to obtain and environmental stimulus responds the extensive concern that more sensitive temperature and pH responsiveness polymer drug carrier receive investigators to external world.
The pH value of human normal tissue is generally 7.4, but when body occurs abnormal, such as, generates heat, infects or canceration, organize and often present lower pH value.Therefore, this pH can be utilized to change preparation pH responsiveness polymer drug carrier, its structure in blood circulation is made to keep complete, do not discharge medicine, and after arriving the diseased regions such as tumour, weak acid environment makes carrier disintegration or structure change and discharge medicine, thus realizes medicine in histiocytic high enrichments such as tumours, improves the availability of medicine to greatest extent.The molecular chain of pH responsive polymer have the acidity that can dissociate or basic group usually.Common monomer has monocarboxylic acid and the ester classes thereof such as methacrylic ester, Methionin and vinylformic acid.PH responsive polymer containing di-carboxylic acid segment has two ionogenic carboxyls on each segment, under equal conditions, lower than the cost of pH responsive polymer of preparation containing monocarboxylic acid segment, but it is less with dicarboxylic acid derivatives to be that monomer prepares the research report of pH responsive polymer at present.Allyl diethyl malonate is one commercial compound, main as medical material and pesticide intermediate, double bond is had in its molecule, radical polymerization can be there is, after two hydrolysis of ester group in its molecule, can form two carboxyls, therefore, allyl diethyl malonate can become the monomer that synthesis has pH responsive polymer.Have not yet to see about allyl diethyl malonate is as the bibliographical information of polymer monomer.
Automatically disease induction substance or pyrogen (as heating, tumour) can there is the change of lower human body temperature in the macromolecule drug delivery system with temperature-responsive, make macromolecular material produce intelligent phase transformation, drug releasing rate is accelerated; When health is normal, namely macromolecular material restores to the original state, and drug release rate also declines thereupon, form response formula medicine releasing system, thus realize the timing of medicine in focal zone, fixed point controllable release, reduce the untoward reaction of medicine to greatest extent, improve the bioavailability of medicine.Poly-(N-caprolactam) (PNVCL) is a kind of temperature-responsive polymkeric substance, its lower critical solution temperature (LCST) is close to the physiological temp of human body, to be hydrolyzed unlike PNVCL with the temperature-responsive polymkeric substance-NIPA (PNIPAM) of current most study and can not to produce poisonous small molecule amine, and the monomer cheaper of PNVCL, therefore, PNVCL has better biocompatibility, may closing to reality application more at biomedicine field.
Because coenocorrelation in body is complicated, development integrates the pH of pH responsiveness and temperature-responsive and temperature dual response polymer is then expected to obtain the pharmaceutical carrier being more suitable for body physiological environment, but pH and the temperature dual responsiveness materials most preparation method of current bibliographical information are complicated, cost of material is more expensive, and industrialization cost is higher.The research that literature search has no pH about being formed by allyl malonic acid and the copolymerization of N-caprolactam and temperature dual response polymer is reported.
Summary of the invention
The object of this invention is to provide new a kind of pH and temperature dual response polymer and its preparation method and application, prepare this multipolymer use raw material cheap and easy to get, preparation method is simple.
The molecular structure of pH of the present invention and temperature dual response polymer is shown below, and its molecular weight is 10000 ~ 30000.
The preparation method of pH of the present invention and temperature dual response polymer is as follows:
A () prepares the multipolymer (PDEAM-co-PNVCL) of allyl diethyl malonate and N-caprolactam:
Diisopropyl azodicarboxylate and N-caprolactam (NVCL) are dissolved in dioxane, the mass ratio of Diisopropyl azodicarboxylate and N-caprolactam is 1:320 ~ 350, is dissolved with the N-caprolactam of 0.1 ~ 0.3g in every milliliter of dioxane; The dioxane solution of allyl diethyl malonate is dripped in stirring in 65 ~ 75 DEG C in a nitrogen atmosphere, add the dioxane solution of allyl diethyl malonate and the volume ratio of Diisopropyl azodicarboxylate (AIBN) and N-caprolactam (NVCL) dioxane solution is 1:1 ~ 2, the mass ratio of allyl diethyl malonate and N-caprolactam is 1:3 ~ 10; After 65 ~ 75 DEG C of polyreactions, product THF dissolves and co-precipitation in sherwood oil, collecting precipitation thing, dissolve with distilled water after organic solvent volatilization is dry, by this aqueous solution molecular weight cut-off be 3500 dialysis tubing dialysis 5 ~ 8 days, obtain the multipolymer (PDEAM-co-PNVCL) of allyl diethyl malonate and N-caprolactam through underpressure distillation and vacuum-drying.
B () prepares the multipolymer (PAMA-co-PNVCL) of allyl malonic acid and N-caprolactam:
NaOH is added in the tetrahydrofuran solution of PDEAM-co-PNVCL, add distilled water again, every milliliter of tetrahydrofuran (THF) is dissolved with 0.02 ~ 0.04gPDEAM-co-PNVCL, and the mass ratio of NaOH and PDEAM-co-PNVCL is 1:1 ~ 1.5, and the volume ratio of distilled water and tetrahydrofuran (THF) is 1:2 ~ 2.5; After 68 ~ 72 DEG C of reaction 48 ~ 52h, be chilled to 0 ~ 5 DEG C, the pH value of reaction mixture is adjusted to 4-5, stir, with dichloromethane extraction, the organic layer separated through underpressure distillation, residuum distilled water dissolve rear molecular weight cut-off be 3500 dialysis tubing dialyse 5 ~ 8 days, underpressure distillation, vacuum-drying obtains the multipolymer (PAMA-co-PNVCL) of allyl malonic acid and N-caprolactam.
It is by through following steps that the preparation method of multipolymer of the present invention optimizes further:
A () prepares the multipolymer (PDEAM-co-PNVCL) of allyl diethyl malonate and N-caprolactam:
Diisopropyl azodicarboxylate and N-caprolactam (NVCL) are dissolved in dioxane, the mass ratio of described Diisopropyl azodicarboxylate and N-caprolactam is 1:320 ~ 350, is dissolved with the N-caprolactam of 0.1 ~ 0.3g in every milliliter of dioxane; Vacuum nitrogen filling gas 3 ~ 5 times, each 30 ~ 60min, 65 ~ 75 DEG C are stirred the lower dioxane solution dripping allyl diethyl malonate, add the dioxane solution of allyl diethyl malonate and the volume ratio of Diisopropyl azodicarboxylate (AIBN) and N-caprolactam (NVCL) dioxane solution is 1:1 ~ 3, the mass ratio of allyl diethyl malonate and N-caprolactam is 1:3 ~ 10; 65 ~ 75 DEG C of polyreaction 20 ~ 30h, product THF to pour in sherwood oil co-precipitation into 2 ~ 5 times after dissolving, collecting precipitation, dissolve with distilled water after organic solvent volatilization is dry, the aqueous solution of product being poured into molecular weight cut-off is in the dialysis tubing of 3500, dialyse 5 ~ 8 days, after underpressure distillation steams water, vacuum-drying obtains the multipolymer (PDEAM-co-PNVCL) of allyl diethyl malonate and N-caprolactam.
B () prepares the multipolymer (PAMA-co-PNVCL) of allyl malonic acid and N-caprolactam:
NaOH is added in the tetrahydrofuran solution of PDEAM-co-PNVCL, add distilled water again, every milliliter of tetrahydrofuran (THF) is dissolved with 0.02 ~ 0.04gPDEAM-co-PNVCL, and the mass ratio of NaOH and PDEAM-co-PNVCL is 1:1 ~ 1.5, and the volume ratio of distilled water and tetrahydrofuran (THF) is 1:2 ~ 2.5; After 70 DEG C of reaction 48 ~ 52h, be chilled to room temperature.Reaction flask is placed in ice-water bath, with the hydrochloric acid of 0.1 ~ 0.2mol/mL by the pH regulator of reaction mixture to 4-5, stir 1 ~ 2h, with dichloromethane extraction 3 ~ 4 times, the organic layer separated steams after organic solvent through underpressure distillation, and it is in the dialysis tubing of 3500 that residuum distilled water is transferred to molecular weight cut-off after dissolving, and dialyses 5 ~ 8 days, after underpressure distillation steams water, vacuum-drying obtains the multipolymer (PAMA-co-PNVCL) of allyl malonic acid and N-caprolactam.
The application of pH of the present invention and temperature dual response polymer is that in water, self-assembly forms nano-micelle, as the Co ntrolled release carrier of podophyllotoxin medicine.
The multipolymer (PAMA-co-PNVCL) of allyl malonic acid prepared by the present invention and N-caprolactam has pH and temperature dual response characteristic, and transmitance measurement result shows, the LCST of multipolymer reduces with the reduction of pH.The LCST of multipolymer also by copolymer concentration and allyl malonic acid and the impact of N-caprolactam segment ratio, reduces with the increase of copolymer concentration; For the aqueous copolymers solution of same concentrations, its LCST raises with the increase of allyl malonic acid content.
The multipolymer (PAMA-co-PNVCL) of allyl malonic acid prepared by the present invention and N-caprolactam has amphipathic, and can self-assembly be micella in selective solvent, the preparation method of its micellar solution be:
The multipolymer (PAMA-co-PNVCL) of 5mg allyl malonic acid and N-caprolactam is dissolved in a small amount of tetrahydrofuran (THF) (THF), after dissolving completely, a small amount of distilled water is added under stirring, steam organic solvent under room temperature, debris proceeds in 5mL volumetric flask and adds distilled water constant volume and obtain 1.0mg/mL micellar solution.
The preparation method of carrier micelle is:
The multipolymer (PAMA-co-PNVCL) of 50mg allyl malonic acid and N-caprolactam and 15mg podophyllotoxin are dissolved in 10mL acetone, be stirred to after dissolving completely, 10mL deionized water is slowly added under stirring, stirring at room temperature removing acetone, surplus solution is centrifugal 30min under 4000r/min, get supernatant liquid drying afterwards obtained copolymer p AMA-co-PNVCL carry podophyllotoxin micella.
Micella is to the carrying drug ratio of medicine and entrapment efficiency determination:
By dried carrier micelle alcohol dilution, obtain the podophyllotoxin solution that micellar concentration is 0.1mg/mL, survey its ultraviolet absorptivity, calculate the content of podophyllotoxin in polypeptide drug-loaded micelle solution, calculate carrying drug ratio and encapsulation rate as follows: carrying drug ratio (%)=(drug loading/carrier amount) × 100%, encapsulation rate (%)=(drug loading/dosage) × 100%.
Test method
The polypeptide drug-loaded micelle solution 15mL that accurate measuring prepares, put into the dialysis tubing that molecular weight cut-off is 3500, be placed in the phosphate buffer soln of 150mLpH5.6 and pH7.4, at 20 DEG C, 37 DEG C and 40 DEG C, constant speed stirs (120r/min) and carries out drug release test.Every 1h, from the release medium dialysis tubing, get 2mL liquid, then supplement the new buffered soln of 2mL.By after the solution example vacuum-drying of taking out, add 4mL dissolve with ethanol, measure its ultraviolet light absorption angle value at 292nm place, linearly regression equation calculation release concentration, the cumulative release percentage of calculating podophyllotoxin.
Beneficial effect of the present invention: the pH that the present invention is formed by allyl malonic acid and the copolymerization of N-caprolactam and temperature dual response polymer, have that raw material is cheap and easy to get, synthetic method is simple, the easily separated purification of product, the advantage such as workable.And self-assembly can form stable ball shaped nano micella in aqueous, this micella has higher drug loading and encapsulation rate to podophyllotoxin, and the pH had podophyllotoxin and temperature dual responsiveness Co ntrolled release performance, can be used for building intelligent controlled drug delivery system.
Accompanying drawing explanation
Fig. 1 is the proton nmr spectra of allyl malonic acid and N-vinyl caprolactam copolymer.
Fig. 2 is allyl malonic acid and the N-vinyl caprolactam copolymer TEM photo of ball shaped nano micella that formed of self-assembly in aqueous.
Fig. 3 is the allyl malonic acid of load podophyllotoxin under differing temps in the buffered soln of pH5.6 and the release profiles of N-vinyl caprolactam copolymer micella.
Fig. 4 is the allyl malonic acid of load podophyllotoxin under differing temps in the buffered soln of pH7.4 and the release profiles of N-vinyl caprolactam copolymer micella.
Embodiment:
Be described in further detail the present invention by embodiment below, but content of the present invention is not limited thereto.
Embodiment one
The dioxane of 1.0gN-caprolactam (NVCL), 3.0mg Diisopropyl azodicarboxylate (AIBN) and 5mL is added in two mouthfuls of flasks of drying, vacuumize, inflated with nitrogen 3 times, flask is put into the oil bath of 70 DEG C, stir the lower dioxane solution (being dissolved in 5mL dioxane by 0.1g allyl diethyl malonate formulated) dripping allyl diethyl malonate, drip and finish, 70 DEG C of polyreaction 24h.With a small amount of THF dissolve polymer, to pour in sherwood oil co-precipitation into 3 times, collecting precipitation, the dry rear water dissolution of organic solvent volatilization, the aqueous solution being poured into molecular weight cut-off is in the dialysis tubing of 3500, dialyse 7 days, vacuum-drying obtains the multipolymer (PDEAM-co-PNVCL) of allyl diethyl malonate and N-caprolactam.
The multipolymer (PDEAM-co-PNVCL) of 1.0g allyl diethyl malonate and N-caprolactam, 35mLTHF, 15mLH is added in the round-bottomed flask of drying
2o and 1.0gNaOH, puts into the oil bath reacting by heating 48h of 70 DEG C.After question response bottle is cooled to room temperature, be placed in ice-water bath, with the HCl solution of 0.1mol/mL, the pH value of reaction mixture be adjusted to 4-5, stir 1h, use CH
2cl
2extraction, the organic layer separated steams after organic solvent through underpressure distillation, it is in the dialysis tubing of 3500 that residuum distilled water is transferred to molecular weight cut-off after dissolving, and dialyse 7 days, vacuum-drying obtains the multipolymer (PAMA-co-PNVCL) of allyl malonic acid and N-caprolactam.Its proton nmr spectra (
1hNMR) Fig. 1 is seen.
Embodiment two
Basic with embodiment one, difference is that allyl diethyl malonate is different from the consumption of N-caprolactam: the dioxane adding 3.0gN-caprolactam (NVCL), 3.0mg Diisopropyl azodicarboxylate (AIBN) and 5mL in two mouthfuls of flasks of drying, vacuumize, inflated with nitrogen 3 times, flask is put into the oil bath of 70 DEG C, stir the lower dioxane solution (being dissolved in 5mL dioxane by 0.5g allyl diethyl malonate formulated) dripping allyl diethyl malonate, drip and finish, 70 DEG C of polyreaction 24h.With a small amount of THF dissolve polymer, to pour in sherwood oil co-precipitation into 3 times, collecting precipitation, the dry rear water dissolution of organic solvent volatilization, the aqueous solution being poured into molecular weight cut-off is in the dialysis tubing of 3500, dialyse 7 days, vacuum-drying obtains the multipolymer (PDEAM-co-PNVCL) of allyl diethyl malonate and N-caprolactam.
The multipolymer (PDEAM-co-PNVCL) of 1.0g allyl diethyl malonate and N-caprolactam, 35mLTHF, 15mLH is added in the round-bottomed flask of drying
2o and 1.0gNaOH, puts into the oil bath reacting by heating 48h of 70 DEG C.After question response bottle is cooled to room temperature, be placed in ice-water bath, with the HCl solution of 0.1mol/mL, the pH value of reaction mixture be adjusted between 4-5, stir 1h, use CH
2cl
2extraction, the organic layer separated steams after organic solvent through underpressure distillation, it is in the dialysis tubing of 3500 that residuum distilled water is transferred to molecular weight cut-off after dissolving, and dialyse 7 days, vacuum-drying obtains the multipolymer (PAMA-co-PNVCL) of allyl malonic acid and N-caprolactam.
Embodiment three
Basic with embodiment one, difference is that allyl diethyl malonate is different from the consumption of N-caprolactam: the dioxane adding 1.0gN-caprolactam (NVCL), 3.0mg Diisopropyl azodicarboxylate (AIBN) and 5mL in two mouthfuls of flasks of drying, vacuumize, inflated with nitrogen 3 times, flask is put into the oil bath of 70 DEG C, stir the lower dioxane solution (being dissolved in 5mL dioxane by 0.3g allyl diethyl malonate formulated) dripping allyl diethyl malonate, drip and finish, 70 DEG C of polyreaction 24h.With a small amount of THF dissolve polymer, to pour in sherwood oil co-precipitation into 3 times, collecting precipitation, the dry rear water dissolution of organic solvent volatilization, the aqueous solution being poured into molecular weight cut-off is in the dialysis tubing of 3500, dialyse 7 days, vacuum-drying obtains the multipolymer (PDEAM-co-PNVCL) of allyl diethyl malonate and N-caprolactam.
The multipolymer (PDEAM-co-PNVCL) of 1.0g allyl diethyl malonate and N-caprolactam, 35mLTHF, 15mLH is added in the round-bottomed flask of drying
2o and 1.0gNaOH, puts into the oil bath reacting by heating 48h of 70 DEG C.After question response bottle is cooled to room temperature, be placed in ice-water bath, with the HCl solution of 0.1mol/mL, the pH value of reaction mixture be adjusted between 4-5, stir 1h, use CH
2cl
2extraction, the organic layer separated steams after organic solvent through underpressure distillation, it is in the dialysis tubing of 3500 that residuum distilled water is transferred to molecular weight cut-off after dissolving, and dialyse 7 days, vacuum-drying obtains the multipolymer (PAMA-co-PNVCL) of allyl malonic acid and N-caprolactam.
Embodiment four
The multipolymer (PAMA-co-PNVCL) of 5mg allyl malonic acid and N-caprolactam is dissolved in 1mL tetrahydrofuran (THF) (THF), after dissolving completely, 3mL distilled water is added under stirring, organic solvent is steamed under room temperature, debris proceeds to constant volume in 5mL volumetric flask and obtains 1.0mg/mL micellar solution, observes for transmission electron microscope (TEM).TEM photo (Fig. 2) shows: allyl malonic acid and N-vinyl caprolactam copolymer are self-assembled into ball shaped nano micella in aqueous.
Embodiment five
The multipolymer of 10mg allyl malonic acid and N-caprolactam is dissolved in a small amount of THF, after dissolving completely, adds a small amount of distilled water, under room temperature, steam THF, surplus solution is proceeded to constant volume in 10mL volumetric flask, obtain the micellar solution of 1.0mg/mL.Pipette the micellar solution of different volumes with liquid-transfering gun in some 5mL volumetric flasks, then in each volumetric flask, add 5 μ L concentration be 4 × 10
-4the acetone soln of M pyrene, room temperature volatilization removing acetone, uses distilled water constant volume, is mixed with the micellar solution of a series of different concns.By the ultrasonic 30min of micellar solution prepared, room temperature records with fluorescent spectrometry after placing 24h
The micelle-forming concentration (CMC) of PAMA-co-PNVCL.The results are shown in Table 1.
The micelle-forming concentration (CMC) of table 1 allyl malonic acid and N-vinyl caprolactam copolymer
Result shows, allyl malonic acid and the N-vinyl caprolactam copolymer of the present invention's development can self-assembly be micella in aqueous, and its micelle-forming concentration (CMC) increases with the increase of allyl malonic acid content.
Embodiment six
With the copolymer carrier micelle of the dried allyl malonic acid of alcohol dilution and N-caprolactam, obtain the podophyllotoxin solution that micellar concentration is 0.1mg/mL, survey its ultraviolet absorptivity, calculate the content of podophyllotoxin in polypeptide drug-loaded micelle solution, calculate carrying drug ratio and encapsulation rate as follows: carrying drug ratio (%)=(drug loading/carrier amount) × 100%, encapsulation rate (%)=(drug loading/dosage) × 100%.The results are shown in Table 2.
The copolymer micelle of table 2 allyl malonic acid and N-caprolactam is to the carrying drug ratio of podophyllotoxin and encapsulation rate
Result shows, the allyl malonic acid of the present invention's development and the copolymer micelle of N-caprolactam have higher carrying drug ratio and encapsulation rate to podophyllotoxin, and the copolymer micelle that N-caprolactam content is many has higher carrying drug ratio and encapsulation rate to podophyllotoxin.
Embodiment seven
The micellar concentration of the multipolymer that the embodiment one prepared by 15mL obtains is that the polypeptide drug-loaded micelle solution of 2.5mg/mL puts into the dialysis tubing that molecular weight cut-off is 3500, be placed in the phosphate buffer soln of 150mLpH5.6, at 20 DEG C, 37 DEG C and 40 DEG C, under constant speed agitation condition, carry out drug release experiment.Every 1h, from the release medium dialysis tubing, get the liquid of 2mL, then supplement the new pH5.6 phosphate buffer soln of 2mL.The solution example taken out is dried, add the dissolve with ethanol solution of 4mL, be determined at the ultraviolet absorptivity at 292nm place, by the concentration-absorbancy linear equation of podophyllotoxin typical curve and podophyllotoxin, calculate the medicament contg in release medium, thus obtain the relation of cumulative release per-cent and time, make release profiles.The results are shown in Figure 3 (A-20 DEG C, A-37 DEG C, A-40 DEG C).
Embodiment eight
Basic with embodiment seven, just the pH of release medium is different: the micellar concentration of the multipolymer that the embodiment one prepared by 15mL obtains is that the polypeptide drug-loaded micelle solution of 2.5mg/mL puts into the dialysis tubing that molecular weight cut-off is 3500, be placed in the phosphate buffer soln of 150mLpH7.4, at 20 DEG C, 37 DEG C and 40 DEG C, under constant speed agitation condition, carry out drug release experiment.Every 1h, from the release medium dialysis tubing, get the liquid of 2mL, then supplement the new pH7.4 phosphate buffer soln of 2mL.The solution example taken out is dried, add the dissolve with ethanol solution of 4mL, be determined at the ultraviolet absorptivity at 292nm place, by the concentration-absorbancy linear equation of podophyllotoxin typical curve and podophyllotoxin, calculate the medicament contg in release medium, thus obtain the relation of cumulative release per-cent and time, make release profiles.The results are shown in Figure 4 (A-20 DEG C, A-37 DEG C, A-40 DEG C).
Embodiment nine
Basic with embodiment seven, just multipolymer is that embodiment two obtains: the micellar concentration of the multipolymer that the embodiment two prepared by 15mL obtains is that the polypeptide drug-loaded micelle solution of 2.5mg/mL puts into the dialysis tubing that molecular weight cut-off is 3500, be placed in the phosphate buffer soln of 150mLpH5.6, at 20 DEG C, 37 DEG C and 40 DEG C, under constant speed agitation condition, carry out drug release experiment.Every 1h, from the release medium dialysis tubing, get the liquid of 2mL, then supplement the new pH5.6 phosphate buffer soln of 2mL.The solution example taken out is dried, add the dissolve with ethanol solution of 4mL, be determined at the ultraviolet absorptivity at 292nm place, by the concentration-absorbancy linear equation of podophyllotoxin typical curve and podophyllotoxin, calculate the medicament contg in release medium, thus obtain the relation of cumulative release per-cent and time, make release profiles.The results are shown in Figure 3 (B-20 DEG C, B-37 DEG C, B-40 DEG C).
Embodiment ten
Basic with embodiment nine, just the pH of release medium is different: the micellar concentration of the multipolymer that the embodiment two prepared by 15mL obtains is that the polypeptide drug-loaded micelle solution of 2.5mg/mL puts into the dialysis tubing that molecular weight cut-off is 3500, be placed in the phosphate buffer soln of 150mLpH7.4, at 20 DEG C, 37 DEG C and 40 DEG C, under constant speed agitation condition, carry out drug release experiment.Every 1h, from the release medium dialysis tubing, get the liquid of 2mL, then supplement the new pH7.4 phosphate buffer soln of 2mL.The solution example taken out is dried, add the dissolve with ethanol solution of 4mL, be determined at the ultraviolet absorptivity at 292nm place, by the concentration-absorbancy linear equation of podophyllotoxin typical curve and podophyllotoxin, calculate the medicament contg in release medium, thus obtain the relation of cumulative release per-cent and time, make release profiles.The results are shown in Figure 4 (B-20 DEG C, B-37 DEG C, B-40 DEG C).
Embodiment 11
Basic with embodiment seven, just multipolymer is that embodiment three obtains: the micellar concentration of the multipolymer that the embodiment two prepared by 15mL obtains is that the polypeptide drug-loaded micelle solution of 2.5mg/mL puts into the dialysis tubing that molecular weight cut-off is 3500, be placed in the phosphate buffer soln of 150mLpH5.6, at 20 DEG C, 37 DEG C and 40 DEG C, under constant speed agitation condition, carry out drug release experiment.Every 1h, from the release medium dialysis tubing, get the liquid of 2mL, then supplement the new pH5.6 phosphate buffer soln of 2mL.The solution example taken out is dried, add the dissolve with ethanol solution of 4mL, be determined at the ultraviolet absorptivity at 292nm place, by the concentration-absorbancy linear equation of podophyllotoxin typical curve and podophyllotoxin, calculate the medicament contg in release medium, thus obtain the relation of cumulative release per-cent and time, make release profiles.The results are shown in Figure 3 (C-20 DEG C, C-37 DEG C, C-40 DEG C).
Embodiment 12
Basic with embodiment 11, just the pH of release medium is different: the micellar concentration of the multipolymer that the embodiment two prepared by 15mL obtains is that the polypeptide drug-loaded micelle solution of 2.5mg/mL puts into the dialysis tubing that molecular weight cut-off is 3500, be placed in the phosphate buffer soln of 150mLpH7.4, at 20 DEG C, 37 DEG C and 40 DEG C, under constant speed agitation condition, carry out drug release experiment.Every 1h, from the release medium dialysis tubing, get the liquid of 2mL, then supplement the new pH7.4 phosphate buffer soln of 2mL.The solution example taken out is dried, add the dissolve with ethanol solution of 4mL, be determined at the ultraviolet absorptivity at 292nm place, by the concentration-absorbancy linear equation of podophyllotoxin typical curve and podophyllotoxin, calculate the medicament contg in release medium, thus obtain the relation of cumulative release per-cent and time, make release profiles.The results are shown in Figure 4 (C-20 DEG C, C-37 DEG C, C-40 DEG C).
Result shows: the copolymer micelle of allyl malonic acid and the N-caprolactam of the present invention's development has pH and temperature dual responsiveness controlled-release function to podophyllotoxin, in the buffered soln of pH5.6 and the rate of release of 40 DEG C than fast with the rate of release of 20 DEG C and 37 DEG C in the buffered soln of pH7.4.
Claims (4)
1. pH and a temperature dual response polymer, is characterized in that molecular structural formula is:
Molecular weight is 10000 ~ 30000.
2. the preparation method of pH as claimed in claim 1 and temperature dual response polymer, is characterized in that as follows:
A () prepares the multipolymer of allyl diethyl malonate and N-caprolactam:
Diisopropyl azodicarboxylate and N-caprolactam are dissolved in dioxane, and the mass ratio of Diisopropyl azodicarboxylate and N-caprolactam is 1:320 ~ 350, is dissolved with the N-caprolactam of 0.1 ~ 0.3g in every milliliter of dioxane; The dioxane solution of allyl diethyl malonate is dripped in stirring in 65 ~ 75 DEG C in a nitrogen atmosphere, add the dioxane solution of allyl diethyl malonate and the volume ratio of Diisopropyl azodicarboxylate and N-caprolactam dioxane solution is 1:1 ~ 2, the mass ratio of allyl diethyl malonate and N-caprolactam is 1:3 ~ 10; After 65 ~ 75 DEG C of polyreactions, product THF dissolves and co-precipitation in sherwood oil, collecting precipitation thing, dissolve with distilled water after organic solvent volatilization is dry, by this aqueous solution molecular weight cut-off be 3500 dialysis tubing dialysis 5 ~ 8 days, obtain the copolymer p DEAM-co-PNVCL of allyl diethyl malonate and N-caprolactam through underpressure distillation and vacuum-drying;
B () prepares the multipolymer of allyl malonic acid and N-caprolactam:
NaOH is added in the tetrahydrofuran solution of PDEAM-co-PNVCL, add distilled water again, every milliliter of tetrahydrofuran (THF) is dissolved with 0.02 ~ 0.04gPDEAM-co-PNVCL, and the mass ratio of NaOH and PDEAM-co-PNVCL is 1:1 ~ 1.5, and the volume ratio of distilled water and tetrahydrofuran (THF) is 1:2 ~ 2.5; After 68 ~ 72 DEG C of reaction 48 ~ 52h, be chilled to 0 ~ 5 DEG C, the pH value of reaction mixture is adjusted to 4-5, stir, with dichloromethane extraction, the organic layer separated through underpressure distillation, residuum distilled water dissolve rear molecular weight cut-off be 3500 dialysis tubing dialyse 5 ~ 8 days, underpressure distillation, vacuum-drying obtains the multipolymer of allyl malonic acid and N-caprolactam.
3. the preparation method of pH as claimed in claim 2 and temperature dual response polymer, is characterized in that as follows:
A () prepares the multipolymer of allyl diethyl malonate and N-caprolactam:
Diisopropyl azodicarboxylate and N-caprolactam are dissolved in dioxane, and the mass ratio of described Diisopropyl azodicarboxylate and N-caprolactam is 1:320 ~ 350, is dissolved with the N-caprolactam of 0.1 ~ 0.3g in every milliliter of dioxane; Vacuum nitrogen filling gas 3 ~ 5 times, each 30 ~ 60min, 65 ~ 75 DEG C are stirred the lower dioxane solution dripping allyl diethyl malonate, add the dioxane solution of allyl diethyl malonate and the volume ratio of Diisopropyl azodicarboxylate and N-caprolactam dioxane solution is 1:1 ~ 3, the mass ratio of allyl diethyl malonate and N-caprolactam is 1:3 ~ 10; 65 ~ 75 DEG C of polyreaction 20 ~ 30h, product THF to pour in sherwood oil co-precipitation into 2 ~ 5 times after dissolving, collecting precipitation, dissolve with distilled water after organic solvent volatilization is dry, the aqueous solution of product being poured into molecular weight cut-off is in the dialysis tubing of 3500, dialyse 5 ~ 8 days, after underpressure distillation steams water, vacuum-drying obtains the copolymer p DEAM-co-PNVCL of allyl diethyl malonate and N-caprolactam;
B () prepares the multipolymer of allyl malonic acid and N-caprolactam:
NaOH is added in the tetrahydrofuran solution of PDEAM-co-PNVCL, add distilled water again, every milliliter of tetrahydrofuran (THF) is dissolved with 0.02 ~ 0.04gPDEAM-co-PNVCL, and the mass ratio of NaOH and PDEAM-co-PNVCL is 1:1 ~ 1.5, and the volume ratio of distilled water and tetrahydrofuran (THF) is 1:2 ~ 2.5; After 70 DEG C of reaction 48 ~ 52h, be chilled to room temperature.Reaction flask is placed in ice-water bath, with the hydrochloric acid of 0.1 ~ 0.2mol/mL by the pH regulator of reaction mixture to 4-5, stir 1 ~ 2h, with dichloromethane extraction 3 ~ 4 times, the organic layer separated steams after organic solvent through underpressure distillation, and it is in the dialysis tubing of 3500 that residuum distilled water is transferred to molecular weight cut-off after dissolving, and dialyses 5 ~ 8 days, after underpressure distillation steams water, vacuum-drying obtains the multipolymer of allyl malonic acid and N-caprolactam.
4. the purposes of pH as claimed in claim 1 and temperature dual response polymer is that in water, self-assembly forms nano-micelle, as the Co ntrolled release carrier of podophyllotoxin medicine.
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| CN110551273A (en) * | 2019-09-17 | 2019-12-10 | 齐鲁工业大学 | Preparation method of dual-stimulus-response polyurethane micelle |
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