CN104231246A - Comb amphiphilic polymer using pulullan as main chain, synthetic process and application thereof - Google Patents
Comb amphiphilic polymer using pulullan as main chain, synthetic process and application thereof Download PDFInfo
- Publication number
- CN104231246A CN104231246A CN201410269117.XA CN201410269117A CN104231246A CN 104231246 A CN104231246 A CN 104231246A CN 201410269117 A CN201410269117 A CN 201410269117A CN 104231246 A CN104231246 A CN 104231246A
- Authority
- CN
- China
- Prior art keywords
- amphipathic nature
- pulullan polysaccharide
- polysaccharide
- nature polyalcohol
- ester monomer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
A series of amphiphilic polymer materials which take pulullan as a main chain and polyester as a branch chain are synthesized. By adopting a novel synthetic method, the synthetic time of the series of amphiphilic polymer materials is shortened to 5 minutes, so that the materials have a relatively high industrial value. The series of amphiphilic polymer materials have multi-aspect application values in the field of medicine transfer such as microsphere and nanoparticle reparations and the like as well as modification of other medicine transfer systems and the like. The series of amphiphilic polymer materials are used for preparing nanoparticles and microsphere conveying transfer medicine or modification medicine transfer carriers such as nanoparticles and microspheres so as to achieve the purpose of increasing the solubility and stability of medicines, improving the curative effect of the medicines and reducing the toxic and side effects of the medicines. The series of materials, which are used as the medicine transfer carriers or modification medicine transfer carriers, can be used for achieving the purpose of liver targeting delivery and temperature sensitive control released delivery at the same time.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to the amphipathic series polymer of pectination that pulullan polysaccharide is main chain, synthetic method and application thereof.
Background technology
Amphipathic nature polyalcohol is that it all has avidity to aqueous phase and oil phase by hydrophilic section and hydrophobic section polymkeric substance dimerous.Under certain environment, amphipathic nature polyalcohol spontaneous assembling can form micella and other self-assembly aggregate.Similar with Small molecular surfactant, when the concentration of amphipathic nature polyalcohol in water meets or exceeds its micelle-forming concentration (CMC) or its critical aggregation concentration (CAC), microphase-separated will be there is in the hydrophobic section under intermolecular hydrogen bond, electrostatic interaction and Van der Waals force etc. promote in molecule and hydrophilic section, spontaneously form hydrophobic section inside, micella or the nanoparticle of what hydrophilic section was outside have typical nucleocapsid structure.Medicine enters the kernel of micella or nanoparticle by modes such as physically trapping, chemical bond and electrostatic interactions, and hydrophilic shell then can increase the stability of micella or nanoparticle.The carrier micelle that self-assembly is formed or nanoparticle are the systems of thermodynamics, dynamic stabilization, have much excellent character, make polymer micelle or nanoparticle become the desirable delivery system of medicine.Polymer micelle or nanoparticle because volume is little and the singularity of surface properties etc., it is not easily absorbed by reticuloendothelial cell and liver excretion, renal excretion, thus the cycling time of prolong drug in blood, improve the bioavailability of medicine.Simultaneously due to high-permeability and the retention effect (EPR effect) of tumor locus, polymer micelle or nanoparticle are as the carrier of cancer therapy drug, singularity due to its volume can reach the effect of passive target, or polymer micelle or nanoparticle can also can be made to have the effect of active targeting by carrying out hydrophilic section modifying by the selection to hydrophilic section purpose, further improving drug effect and reducing toxic side effect.Therefore polymer micelle or nanoparticle boundless as the application prospect of pharmaceutical carrier.
Amphipathic nature polyalcohol also has important using value and potentiality in other direction, as: amphipathic nature material can be used for preparing the slow controlled release carriers such as hydrophilic gel, nanoparticle and microballoon; And by amphipathic nature polyalcohol, the system such as nanoparticle and microballoon is modified, the problems such as the burst drug release that the destruction on the system such as nanoparticle and microballoon surface can be avoided to cause or incomplete release; Also there is one seat at tissue engineering bracket material field amphipathic nature polyalcohol simultaneously; A lot of research also demonstrates the using value of amphipathic nature polyalcohol at medical diagnostic field.The development potentiality of amphipathic nature polyalcohol should not be underestimated.
Amphipathic nature material as pharmaceutical carrier is normally made up of good biocompatibility and biodegradable material.Be that the amphipathic nature polyalcohol that framework modification generates receives publicity gradually as the research of pharmaceutical carrier with natural polysaccharide, mainly due to its wide material sources, cheap and easy to get, there is good biocompatibility and biodegradability, and also there is the function of decorated nanometer grain carrier surface, cytophagous engulfing can be reduced, obvious prolong drug retention time in vivo, increases curative effect of medication.Natural polysaccharide mainly comprises chitosan, dextran, pulullan polysaccharide and derivatived cellulose etc., is water-soluble polysaccharide.Wherein pulullan polysaccharide is a kind of special microbial polysaccharide, there is good film forming, become fiber, choke, bonding, easy processing, the characteristic such as nontoxic, be widely used in the fields such as medicine, food, light industry, chemical industry and oil.Pulullan polysaccharide can be combined with the galactosylated acceptor of surface of hepatocytes, has liver target, can realize the Liver targeting active transfer of medicine.
Polyester also receives as the class in synthetic polymer and pays close attention to widely.As poly(lactic acid), polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone, PTMC and poly-butyrolactone etc.The good characteristics such as these polyester good biocompatibility, biodegradable and degraded products thereof are nontoxic make it be widely used at biomedicine field.
Therefore synthesising macromolecule copolymer polyester material is selected to modify natural high molecular polymer pulullan polysaccharide in advance, to the biodegradability of both comprehensive utilizations, good biocompatibility and nontoxic etc. denominator, and the liver target of pulullan polysaccharide, strong and the good film-forming property of tackiness etc., biodegradable amphipathic nature polyalcohol is obtained to synthesis, by selecting pulullan polysaccharide molecular weight, the selection of the ratio of polyester kind and copolyesters etc. obtains amphipathic nature polyalcohol of different nature series with the control of adjustment and reaction conditions to synthesizing, this serial amphipathic nature polyalcohol is expected in useful for drug delivery, tissue engineering bracket material, the field such as medical diagnosis on disease and packaging material for food is applied.
Much study at present and carry out hydrophobically modifiedly preparing amphipathic nature material to it on the basis of pulullan polysaccharide as hydrophilic section, but the correlative study achievement of modifying Propiram using polyester as hydrophobic section is very limited.Donabedian equal 1998 first successfully synthesis obtain polycaprolactone and polylactic acid modified pulullan polysaccharide, but this synthetic method is consuming time longer, and do not have the research [Donabedian of this materials application aspect, D. H., & McCarthy, S. P. (1998). Acylation of Pullulan by Ring-Opening of Lactones.
macromolecules, 31(4), 1032-1039.].And Ohya etc. have employed two kinds of different synthetic schemes synthesis and obtain polylactic acid modified pulullan polysaccharide, and have studied the aggregation properties of this polymkeric substance in water, but these two kinds of synthetic schemess are all three-step reaction, more loaded down with trivial details [Ohya, Y., Maruhashi, S., & Ouchi, T. (1998). Graft polymerization of L-lactide on pullulan through the trimethylsilyl protection method and degradation of the graft copolymers.
macromolecules, 31(14), 4662-4665; Ouchi, T., Minari, T., & Ohya, Y. (2004). Synthesis of poly (L-lactide)-grafted pullulan through coupling reaction between amino group end-capped poly (L-lactide) and carboxymethyl pullulan and its aggregation behavior in water.
journal of Polymer Science Part A:Polymer Chemistry, 42(21), 5482-5487.].Sub-for octoate catalyst tin triethylamine substitutes by Cho etc. on the basis that Donabedian studies, synthesize the amphipathic nature polyalcohol of polylactic acid modified Propiram, reaction times was foreshortened to 12h [Cho from 6 days, J.-K., Park, W., & Na, K. (2009). Self-organized nanogels from pullulan-g-poly (L-lactide) synthesized by one-pot method:Physicochemical characterization and in vitro doxorubicin release.
journal of applied polymer science, 113(4), 2209-2216.], next have studied the character of this amphipathic nature polyalcohol self-assembly and control the character [Seo of its release as the transmission carrier of Zorubicin and temperature sensitive, S., Lee, C.-S., Jung, Y.-S., & Na, K. (2012). Thermo-sensitivity and triggered drug release of polysaccharide nanogels derived from pullulan-g-poly (L-lactide) copolymers.
carbohydrate polymers, 87(2), 1105-1111.].But it has synthesized the pulullan polysaccharide of poly(lactic acid) grafting and has only applied as the nano-carrier of Zorubicin, do not carry out synthesis and other many-sided application of the pulullan polysaccharide of other polyester modification.Also there is scholar to be directly connected to by PLGA on the hydroxyl of pulullan polysaccharide by esterification and obtain amphipathic nature polyalcohol [Jeong, Y. I., H. S. Na, J. S. Oh, K. C. Choi, C. E. Song & H. C. Lee (2006) Adriamycin release from self-assembling nanospheres of poly (DL-lactide-co-glycolide)-grafted pullulan.
international Journal of Pharmaceutics,322
,154-160.].But this synthetic method cost is high, and be not suitable for amplifying production.The achievement in research of Propiram and the application of associated materials is modified at present there are no other polyester material.
Summary of the invention
The object of the invention is:
1, the amphipathic series polymer of pectination be made up of the polyester material of the pulullan polysaccharide of hydrophilic section and hydrophobic section is provided.
2, the fast synthesis method of this serial pectination amphipathic nature polyalcohol is provided.
3, provide this serial pectination amphipathic nature polyalcohol as pharmaceutical carrier or its application of modifying, long circulating, Liver targeting, raising stability and temperature sensitive can be played and control the effects such as release.
The molecular weight of pulullan polysaccharide is 2-2000000g/mol, and preferred molecular weight is 5-200000g/mol.
Polyester as hydrophobic section can be poly(lactic acid), Poly(D,L-lactide-co-glycolide, PTMC, poly(lactic acid)-trimethylene carbonate multipolymer and poly-hydroxyl ethanol acid-trimethylene carbonate multipolymer etc.
Its synthetic method of amphipathic nature polyalcohol is:
(1) precision takes pulullan polysaccharide in eggplant type bottle, and add in 8mL organic solvent to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve;
(2), after polysaccharide dissolves, add ester monomer, under nitrogen protection condition, heated and stirred makes whole dissolving;
(3) ester monomer dissolves and adds catalyzer after mixing with pulullan polysaccharide, reacts under specified conditions;
(4), after question response terminates, adopt proper method to process reaction solution, obtain amphipathic nature polyalcohol.
Organic solvent used in this reactions steps (1) can be the mixed solvent of one or more in dimethyl sulfoxide (DMSO), dimethyl formamide and N,N-DIMETHYLACETAMIDE.
In this reactions steps (2), the concentration of Propiram is 10%.
The hydroxyl of pulullan polysaccharide in this reaction: ester monomer: catalyzer=100:40-200:0.05-0.2.
In this reactions steps (3), catalyzer can be stannous octoate, triethylamine and zinc lactate etc.
The synthesis of material is carried out by traditional heating or microwave-assisted, preferred Microwave-assisted synthesis in this reactions steps (3).
Can obtain the amphipathic nature polyalcohol of different degree of substitution by adjusting the reaction conditionss such as the ratio of the ratio of microwave output power, ester monomer and catalyzer, pulullan polysaccharide hydroxyl and ester monomer and reaction solvent, it can be used for modified medicaments transfer system or self is as the transmission carrier of medicine.
Microwave output power be 150W, the ratio of ester monomer and catalyzer is 0.1:100, the ratio of pulullan polysaccharide hydroxyl and ester monomer is 60:100 or 100:100, when reaction solvent is dimethyl sulfoxide (DMSO), the amphipathic nature polyalcohol obtained can modified medicaments transfer system or self as medicine nanometer transmit carrier.
Microwave output power be 150W, the ratio of ester monomer and catalyzer is 0.1:100-0.2:100, the ratio of pulullan polysaccharide hydroxyl and ester monomer is 60:100-100:100, when reaction solvent is dimethyl sulfoxide (DMSO), the substitution value 0.9-1.1 of amphipathic nature polyalcohol.
The invention has the advantages that synthesis obtains the amphipathic nature polyalcohol material that a series of pulullan polysaccharide is main chain; And make the generated time of this serial amphipathic nature polyalcohol material foreshorten to 5min by adopting new synthetic method.The amphipathic nature polyalcohol of different degree of substitution can be obtained by controlling reaction conditions.
This serial amphipathic nature material has many-sided using value in useful for drug delivery field, as the modification etc. of microball preparation, nanoparticle and other drug delivery system; This serial amphipathic nature material is prepared into nanoparticle, medicine is transmitted in microballoon conveying or modified medicaments transmission carrier reaches the objects such as solubleness, stability, the curative effect of raising medicine and the toxic side effect of minimizing medicine increasing medicine as nanoparticle and microballoon etc.; This series material transmits carrier as drug carrier system or modified medicaments can reach Liver targeting transmission administration and the object that simultaneously can realize the administration of temperature sensitive Co ntrolled release.
Accompanying drawing illustrates:
The composition principle schematic diagram of Fig. 1 amphipathic nature polyalcohol
Fig. 2 pulullan polysaccharide and amphipathic nature polyalcohol
1h NMR collection of illustrative plates (a: pulullan polysaccharide; B: embodiment 9; C: embodiment 10; D: embodiment 11)
FT-IR collection of illustrative plates (a: pulullan polysaccharide of Fig. 3 pulullan polysaccharide and amphipathic nature polyalcohol; B: embodiment 9; C: embodiment 10; D: embodiment 11)
The CAC(a of Fig. 4 amphipathic nature polyalcohol: embodiment 10; B: embodiment 11)
Particle size distribution figure (the PL-8: embodiment 10 synthesis obtains nanoparticle prepared by material of drug-carrying nanometer particle prepared by Fig. 5 amphipathic nature polyalcohol; PL-9: embodiment 11 synthesis obtains nanoparticle prepared by material)
Transmission electron microscope picture (a: embodiment 10 synthesis obtains nanoparticle prepared by material of drug-carrying nanometer particle prepared by Fig. 6 amphipathic nature polyalcohol and microballoon; B: embodiment 11 synthesis obtains nanoparticle prepared by material; C: embodiment 15 thus obtained microsphere)
Release profiles (embodiment 12) under the differing temps of Fig. 7 curcumin nanoparticles
The large raticide moving curve of Fig. 8 curcumin nanoparticles preparation (embodiment 17).
Embodiment
Embodiment 1:
Precision takes pulullan polysaccharide (Mw:0.5 × 10
5g/mol) 1.600g is in eggplant type bottle; add in 80mL DMSO to above-mentioned eggplant type bottle; under nitrogen protection condition, heated and stirred makes polysaccharide dissolve; add rac-Lactide 1.710g; under nitrogen protection condition, heated and stirred makes whole dissolving; add the sub-tin 6.0mg of octoate catalyst, vacuum nitrogen filling gas repeatedly, successive reaction 6 days in 80 DEG C of oil baths.After question response terminates, under constantly stirring, add precipitation solvent (methylene dichloride: ethyl acetate=2:3, v/v) 900mL, make amphipathic nature polyalcohol Precipitation, vacuum-drying 48h under 40 DEG C of conditions.
Embodiment 2:
Precision takes pulullan polysaccharide (Mw:0.5 × 10
5g/mol) 4.000g is in eggplant type bottle; add in 80mL DMF to above-mentioned eggplant type bottle; under nitrogen protection condition, heated and stirred makes polysaccharide dissolve; add glycollide 5.156; under nitrogen protection condition, heated and stirred makes whole dissolving; add catalyst of triethylamine 7.5mg, repeatedly vacuum nitrogen filling gas, successive reaction 12h in 80 DEG C of oil baths.After question response terminates, dialysis removing reaction solvent and catalyzer are carried out to reaction solution, vacuum-drying 48h under 40 DEG C of conditions.
Embodiment 3:
Precision takes pulullan polysaccharide (Mw:1.0 × 10
5g/mol) 8.000g is in eggplant type bottle, add in 80mL DMAC to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve, add caprolactone 13.528g, under nitrogen protection condition, heated and stirred makes whole dissolving, adds catalyzer zinc lactate 88.1mg, repeatedly vacuum nitrogen filling gas, react in single mold microwave reactor, reaction conditions is: power 200W; Temperature: 80 DEG C; Duration: 5min.After question response terminates, under constantly stirring, add precipitation solvent (methylene dichloride: acetone=1:5, v/v) 1.5L, make amphipathic nature polyalcohol Precipitation, vacuum-drying 48h under 40 DEG C of conditions.
Embodiment 4:
Precision takes pulullan polysaccharide (Mw:1.5 × 10
5g/mol) 12.000g is in eggplant type bottle, add in 80mL DMF to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve, add glycollide 25.778g and rac-Lactide 32.029g, under nitrogen protection condition, heated and stirred makes whole dissolving, adds the sub-tin 45.0mg of octoate catalyst, vacuum nitrogen filling gas repeatedly, react in single mold microwave reactor, reaction conditions is: power 200W; Temperature: 80 DEG C; Duration: 5min.After question response terminates, dialysis removing reaction solvent and catalyzer are carried out to reaction solution, vacuum-drying 48h under 40 DEG C of conditions.
Embodiment 5:
Precision takes pulullan polysaccharide (Mw:2.0 × 10
5g/mol) 16.000g is in eggplant type bottle; add in 80mL DMSO to above-mentioned eggplant type bottle; under nitrogen protection condition, heated and stirred makes polysaccharide dissolve; add trimethylene carbonate 12.100g; under nitrogen protection condition, heated and stirred makes whole dissolving; add catalyst of triethylamine 59.9mg, repeatedly vacuum nitrogen filling gas, successive reaction 24h in 80 DEG C of oil baths.After question response terminates, under constantly stirring, add precipitation solvent (tetrahydrofuran (THF): ethyl acetate=1:1, v/v) 1L, make amphipathic nature polyalcohol Precipitation, vacuum-drying 48h under 40 DEG C of conditions.
Embodiment 6:
Precision takes pulullan polysaccharide (Mw:1.2 × 10
5g/mol) 10.000g is in eggplant type bottle, add in 80mL DMAC to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve, add rac-Lactide 26.691g, under nitrogen protection condition, heated and stirred makes whole dissolving, adds the sub-tin 75.0mg of octoate catalyst, vacuum nitrogen filling gas repeatedly, react in single mold microwave reactor, reaction conditions is: power 150W; Temperature: 80 DEG C; Duration: 5min.After question response terminates, under constantly stirring, add precipitation solvent (methylene dichloride: ethyl acetate=2:3, v/v) 900mL, make amphipathic nature polyalcohol Precipitation, vacuum-drying 48h under 40 DEG C of conditions.
Embodiment 7:
Precision takes pulullan polysaccharide (Mw:1.2 × 10
5g/mol) 10.000g is in eggplant type bottle, add in 80mL DMAC to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve, add butyrolactone 12.754g, under nitrogen protection condition, heated and stirred makes whole dissolving, adds catalyzer zinc lactate 55.1mg, repeatedly vacuum nitrogen filling gas, react in single mold microwave reactor, reaction conditions is: power 100W; Temperature: 80 DEG C; Duration: 5min.After question response terminates, under constantly stirring, add precipitation solvent (tetrahydrofuran (THF): ethyl acetate=1:1, v/v) 1L, make amphipathic nature polyalcohol Precipitation, vacuum-drying 48h under 40 DEG C of conditions.
Embodiment 8:
Precision takes pulullan polysaccharide (Mw:2.0 × 10
5g/mol) 12.000g is in eggplant type bottle, add in 80mL DMF to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve, add Isosorbide-5-Nitrae-dioxane-diox 22.687g, under nitrogen protection condition, heated and stirred makes whole dissolving, add catalyst of triethylamine 22.487mg, vacuum nitrogen filling gas repeatedly, reacts in single mold microwave reactor, and reaction conditions is: power 200W; Temperature: 80 DEG C; Duration: 5min.After question response terminates, dialysis removing reaction solvent and catalyzer are carried out to reaction solution, vacuum-drying 48h under 40 DEG C of conditions.
Embodiment 9:
Precision takes pulullan polysaccharide (Mw:1.2 × 10
5g/mol) 12.000g is in eggplant type bottle, add in 80mL DMSO to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve, add rac-Lactide 27.225g, under nitrogen protection condition, heated and stirred makes whole dissolving, adds the sub-tin 180.04mg of octoate catalyst, vacuum nitrogen filling gas repeatedly, react in single mold microwave reactor, reaction conditions is: power 150W; Temperature: 80 DEG C; Duration: 5min.After question response terminates, under constantly stirring, add precipitation solvent (methylene dichloride: ethyl acetate=2:3, v/v) 900mL, make amphipathic nature polyalcohol Precipitation, vacuum-drying 48h under 40 DEG C of conditions, resulting polymers substitution value is 1.1.
Embodiment 10:
Precision takes pulullan polysaccharide (Mw:1.2 × 10
5g/mol) 12.000g is in eggplant type bottle, add in 80mL DMSO to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve, add rac-Lactide 19.217g, under nitrogen protection condition, heated and stirred makes whole dissolving, adds the sub-tin 90.02mg of octoate catalyst, vacuum nitrogen filling gas repeatedly, react in single mold microwave reactor, reaction conditions is: power 150W; Temperature: 80 DEG C; Duration: 5min.After question response terminates, under constantly stirring, add precipitation solvent (methylene dichloride: ethyl acetate=2:3, v/v) 900mL, make amphipathic nature polyalcohol Precipitation, vacuum-drying 48h under 40 DEG C of conditions, resulting polymers substitution value is 0.9.
Embodiment 11:
Precision takes pulullan polysaccharide (Mw:1.2 × 10
5g/mol) 12.000g is in eggplant type bottle, add in 80mL DMSO to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve, add rac-Lactide 32.029g, under nitrogen protection condition, heated and stirred makes whole dissolving, adds the sub-tin 90.02mg of octoate catalyst, vacuum nitrogen filling gas repeatedly, react in single mold microwave reactor, reaction conditions is: power 150W; Temperature: 80 DEG C; Duration: 5min.After question response terminates, under constantly stirring, add precipitation solvent (methylene dichloride: ethyl acetate=2:3, v/v) 900mL, make amphipathic nature polyalcohol Precipitation, vacuum-drying 48h under 40 DEG C of conditions, resulting polymers substitution value is 1.0.
Embodiment 12:
Adopt fluorescence probe method to synthesize to embodiment 10 and embodiment 11 mensuration that the material obtained carries out its critical aggregation concentration (CAC), the CAC that embodiment 10 and 11 synthesizes the material obtained is respectively 7.9 and 5.8mg/L.
Embodiment 13:
Accurate embodiment 10 and the embodiment 1 of taking synthesizes the amphipathic nature polyalcohol material 1.000g that obtains in eggplant type bottle respectively, measure in 100 mL methyl alcohol to above-mentioned eggplant type bottle, after material dissolves, precision takes curcumine 100 mg in the solution of above-mentioned materials, after curcumine all dissolves and mixes with material solution, methanol removed by evaporation is rotated under the water bath condition of 45 DEG C, to be obtained containing after the amphipathic nature polyalcohol material film of curcumine, add the glucose solution of 5% of 50 mL to above-mentioned eggplant type bottle, aquation 30 min, the solution obtained crosses 0.22 μm of sterilised membrane filter, namely curcumin nanoparticles solution is obtained.And the particle diameter of nanoparticle is measured by dynamic light scattering method, adopt the morphological specificity of transmission electron microscope observing nanoparticle.Result shows that the average diameter of the nanoparticle adopting embodiment 10 and 11 to prepare is respectively 215.8 and 173.6nm, and its polydispersity coefficient is respectively 0.391 and 0.294 and shows that the size distribution of the two is narrower.Transmission electron microscope results shows that prepared nanoparticle becomes similar spheroidal.
Embodiment 14:
Precision takes embodiment 1 and synthesizes the amphipathic nature polyalcohol material 1.000g that obtains in eggplant type bottle, measure 100 mL mixing solutionss (methyl alcohol: methylene dichloride=1:1, v/v) to above-mentioned eggplant type bottle, after material dissolves, precision takes taxol 100 mg in the solution of above-mentioned materials, after taxol all dissolves and mixes with material solution, evaporating organic solvent is rotated under the water bath condition of 45 DEG C, to be obtained containing after the amphipathic nature polyalcohol material film of taxol, add the glucose solution of 5% of 50 mL to above-mentioned eggplant type bottle, aquation 30 min, the solution obtained crosses 0.22 μm of sterilised membrane filter, namely effect of nano-paclitaxel solution is obtained.The solubleness of taxol is made to be increased to 2.04mg/mL.
Embodiment 15:
Precision takes embodiment 9 and synthesizes amphipathic nature polyalcohol material 500 mg that obtains in eggplant type bottle, measure in 100 mL methyl alcohol to above-mentioned eggplant type bottle, after material dissolves, precision takes curcumine 50 mg in the solution of above-mentioned materials, after curcumine all dissolves and mixes with material solution, this mixing solutions is dropped in 500 mL distilled water.Above-mentioned solution is rotated methanol removed by evaporation under the water bath condition of 45 DEG C, centrifugal 10 min of 10000rm, supernatant discarded, add the acetone of certain volume, centrifugal 10 min of vortex 3min, 10000rm, supernatant discarded, add the distilled water of certain volume again, vortex 3min, namely last supernatant discarded obtains curcumine microballoon.And pass through the morphological specificity of transmission electron microscope observing microballoon.Result shows that its particle diameter of prepared microballoon is less than 2 μm, becomes class spherical.
Embodiment 16:
After curcumin nanoparticles embodiment 9 prepared adopts normal saline dilution 10 times, packing is in the EP pipe of some quantity 2 mL, the EP pipe of curcumin nanoparticles solution will be housed, be divided into three groups, be placed in 25 respectively, in the thermostatic water bath vibrator of 37 and 42 DEG C, respectively at 0, 0.25, 0.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144, 168, 192 and 216h take out 3 EP pipe, centrifugal 10 min of 8000rpm, get supernatant solution, curcumine assay is carried out after adopting DMSO to dilute suitable multiple, and calculate the cumulative release amount of curcumine.Result shows that this nanoparticle has temperature-sensitive controlled-release effect.
Embodiment 17:
Get healthy male Wistar rat (weight 200 ~ 230g).Before administration, fasting 12 h, freely drinks water.Gavage gives containing curcumin nanoparticles (embodiment 9) CUR-PLG and curcumin suspension CUR-HX respectively, and dosage is respectively 20 and 100 mgkg
-1, two groups respectively at after administration 0.08,0.25,0.5,1,2,4,8,12,24 h and 0.08,0.16,0.25,0.5,1,2,4,8,12,24h gets blood 0.6 mL through retroorbital venous clump, puts and scribbles in the centrifuge tube of heparin, centrifugal 10 min of 3500 prm, separated plasma, preserves in-20 DEG C of refrigerators, until analyze.U-HPLC/Q-TOF MS method is adopted to measure its Plasma Concentration.
Serum level-time curve that gavage gives curcumin nanoparticles and suspensoid is shown in Fig. 8, and result shows that curcumin nanoparticles can improve the Oral Administration in Rats bioavailability of curcumine significantly.Be that contrast curcumin nanoparticles makes the oral relative bioavailability of curcumine bring up to 3547% with curcumin suspension.Very fast from the absorption of the visible Cur of Tmax, this may be because the particle diameter of curcumin nanoparticles is less thus improve the uptake rate of curcumine and the degree of absorption.And it is bimodal to find out that CUR-PLG occurs from medicine moving curve, first peak may produce at stomach and duodenal absorption due to medicine, and second peak may be the bioavailability enough significantly being carried curcumine by lymph at the visible curcumin nanoparticles that the absorption of jejunum and ileum produces.
Claims (14)
1. a pectination amphipathic nature polyalcohol, is made up of the pulullan polysaccharide of hydrophilic section and the polyester material of hydrophobic section.
2. polymkeric substance according to claim 1, is characterized in that the molecular weight of pulullan polysaccharide is at 20000-2000000g/mol.
3. pulullan polysaccharide according to claim 2, its molecular weight is at 50000-200000g/mol.
4. polymkeric substance according to claim 1, is characterized in that: the polyester material of hydrophobic section can be poly(lactic acid), Poly(D,L-lactide-co-glycolide, PTMC, poly(lactic acid)-trimethylene carbonate multipolymer and poly-hydroxyl ethanol acid-trimethylene carbonate multipolymer or its mixed copolymer.
5. the synthetic method of amphipathic nature polyalcohol according to claim 1:
(1) precision takes pulullan polysaccharide in eggplant type bottle, and add in 8mL organic solvent to above-mentioned eggplant type bottle, under nitrogen protection condition, heated and stirred makes polysaccharide dissolve;
(2), after polysaccharide dissolves, add ester monomer, under nitrogen protection condition, heated and stirred makes whole dissolving;
(3) ester monomer dissolves and adds catalyzer after mixing with pulullan polysaccharide, reacts under specified conditions;
(4), after question response terminates, adopt proper method to process reaction solution, obtain amphipathic nature polyalcohol.
6. method according to claim 5, is characterized in that organic solvent used in step (1) can for the mixed solvent of one or more in dimethyl sulfoxide (DMSO), dimethyl formamide and N,N-DIMETHYLACETAMIDE.
7. method according to claim 5, is characterized in that the concentration of Propiram in step (2) is 10%.
8. method according to claim 5, is characterized in that the hydroxyl of pulullan polysaccharide: ester monomer: catalyzer=100:40-200:0.05-0.2.
9. method according to claim 5, is characterized in that in step (3), catalyzer can be stannous octoate, triethylamine and zinc lactate etc.
10. method according to claim 5, is characterized in that passing through Microwave-assisted synthesis in step (3).
11. methods according to claim 5, is characterized in that the reaction conditionss such as ratio by adjusting the ratio of microwave output power, ester monomer and catalyzer, pulullan polysaccharide hydroxyl and ester monomer and reaction solvent can obtain the amphipathic nature polyalcohol of different degree of substitution.
12. reaction conditionss according to claim 11, microwave output power be 150W, the ratio of ester monomer and catalyzer is 0.1:100-0.2:100, the ratio of pulullan polysaccharide hydroxyl and ester monomer is 60:100-100:100, when reaction solvent is dimethyl sulfoxide (DMSO), substitution value 09-1.1.
13. amphipathic nature polyalcohols according to claim 1, can play long circulating, Liver targeting, raising stability and temperature sensitive and control the effects such as release.
14. can modified medicaments transfer system or self is as the transmission carrier of medicine according to the obtained amphipathic nature polyalcohol of claim 12.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410269117.XA CN104231246A (en) | 2014-06-17 | 2014-06-17 | Comb amphiphilic polymer using pulullan as main chain, synthetic process and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410269117.XA CN104231246A (en) | 2014-06-17 | 2014-06-17 | Comb amphiphilic polymer using pulullan as main chain, synthetic process and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104231246A true CN104231246A (en) | 2014-12-24 |
Family
ID=52220220
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410269117.XA Pending CN104231246A (en) | 2014-06-17 | 2014-06-17 | Comb amphiphilic polymer using pulullan as main chain, synthetic process and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104231246A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566649A (en) * | 2016-03-03 | 2016-05-11 | 山东理工大学 | Preparation method of PVA (Polyvinyl Alcohol)-polypeptide-PCL (Polycaprolactone)-PTMC (Poly Trimethylene Carbonate) three-grafting copolymer |
| CN106065047A (en) * | 2016-07-14 | 2016-11-02 | 山东省肿瘤防治研究院 | A kind of Liver targeting cationic polymer and preparation method and application |
| CN107158393A (en) * | 2017-06-20 | 2017-09-15 | 苏州乔纳森新材料科技有限公司 | A kind of copolymerized material of pulullan polysaccharide PLA and preparation method thereof |
| CN110547459A (en) * | 2019-10-12 | 2019-12-10 | 山东省食品发酵工业研究设计院 | method for preparing solid octadecanoyl octadecanoic acid pullulan ester oil-carrying nano particles by adopting freeze drying |
| CN110558558A (en) * | 2019-10-12 | 2019-12-13 | 山东省食品发酵工业研究设计院 | method for preparing solid octadecanoyl octadecanoic acid pullulan ester oil-carrying nano particles by spray drying |
| CN110558559A (en) * | 2019-10-12 | 2019-12-13 | 山东省食品发酵工业研究设计院 | preparation method of Chinese forest frog oil capsule |
| CN110692962A (en) * | 2019-10-12 | 2020-01-17 | 山东省食品发酵工业研究设计院 | Preparation method of winter jujube composite powder containing DHA algae oil nanoparticles |
| CN115534471A (en) * | 2022-10-10 | 2022-12-30 | 上海同新服材新材料科技有限公司 | Biodegradable express delivery bag containing plant polysaccharide and preparation method thereof |
-
2014
- 2014-06-17 CN CN201410269117.XA patent/CN104231246A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566649A (en) * | 2016-03-03 | 2016-05-11 | 山东理工大学 | Preparation method of PVA (Polyvinyl Alcohol)-polypeptide-PCL (Polycaprolactone)-PTMC (Poly Trimethylene Carbonate) three-grafting copolymer |
| CN106065047A (en) * | 2016-07-14 | 2016-11-02 | 山东省肿瘤防治研究院 | A kind of Liver targeting cationic polymer and preparation method and application |
| CN107158393A (en) * | 2017-06-20 | 2017-09-15 | 苏州乔纳森新材料科技有限公司 | A kind of copolymerized material of pulullan polysaccharide PLA and preparation method thereof |
| CN110547459A (en) * | 2019-10-12 | 2019-12-10 | 山东省食品发酵工业研究设计院 | method for preparing solid octadecanoyl octadecanoic acid pullulan ester oil-carrying nano particles by adopting freeze drying |
| CN110558558A (en) * | 2019-10-12 | 2019-12-13 | 山东省食品发酵工业研究设计院 | method for preparing solid octadecanoyl octadecanoic acid pullulan ester oil-carrying nano particles by spray drying |
| CN110558559A (en) * | 2019-10-12 | 2019-12-13 | 山东省食品发酵工业研究设计院 | preparation method of Chinese forest frog oil capsule |
| CN110692962A (en) * | 2019-10-12 | 2020-01-17 | 山东省食品发酵工业研究设计院 | Preparation method of winter jujube composite powder containing DHA algae oil nanoparticles |
| CN115534471A (en) * | 2022-10-10 | 2022-12-30 | 上海同新服材新材料科技有限公司 | Biodegradable express delivery bag containing plant polysaccharide and preparation method thereof |
| CN115534471B (en) * | 2022-10-10 | 2024-05-10 | 上海同新服材新材料科技有限公司 | Biodegradable express bag containing plant polysaccharide and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104231246A (en) | Comb amphiphilic polymer using pulullan as main chain, synthetic process and application thereof | |
| Afshar et al. | Preparation and characterization of sodium alginate/polyvinyl alcohol hydrogel containing drug-loaded chitosan nanoparticles as a drug delivery system | |
| Deng et al. | Injectable thermosensitive hydrogel systems based on functional PEG/PCL block polymer for local drug delivery | |
| Liu et al. | Acetylated debranched starch micelles as a promising nanocarrier for curcumin | |
| CN101961494B (en) | Star polymer nano-medicament carrier preparation used for intracellular medicament delivery and preparation method thereof | |
| Lakkakula et al. | Cationic cyclodextrin/alginate chitosan nanoflowers as 5-fluorouracil drug delivery system | |
| Papadimitriou et al. | Novel self-assembled core–shell nanoparticles based on crystalline amorphous moieties of aliphatic copolyesters for efficient controlled drug release | |
| Pereira et al. | Starch-based microspheres for sustained-release of curcumin: preparation and cytotoxic effect on tumor cells | |
| Vassiliou et al. | Facile synthesis of polyester-PEG triblock copolymers and preparation of amphiphilic nanoparticles as drug carriers | |
| Wang et al. | Ginkgo biloba extracts-loaded starch nano-spheres: preparation, characterization, and in vitro release kinetics | |
| Brzeziński et al. | Microfluidic-assisted nanoprecipitation of biodegradable nanoparticles composed of PTMC/PCL (co) polymers, tannic acid and doxorubicin for cancer treatment | |
| CN103751148B (en) | A kind of antineoplastic nanoparticle with targeting and slow releasing function by carrier of amphiphilic polyurethane and preparation method thereof | |
| Wang et al. | Amphiphilic carboxylated cellulose-g-poly (l-lactide) copolymer nanoparticles for oleanolic acid delivery | |
| CN103073730B (en) | CA-(PLA-ran-PLC-b-PEC) periodic copolymer and preparation method and application thereof | |
| Mooguee et al. | Synthesis and in vitro release of adriamycin from star-shaped poly (lactide-co-glycolide) nano-and microparticles | |
| CN105879052B (en) | A kind of method that pectin-multi-arm polyethylene glycol self assembly prepares Nano medication | |
| CN107793573B (en) | Preparation method of hybrid amphiphilic star-shaped copolymer nano micelle | |
| CN103159959B (en) | Star-like amphipathic multipolymer of a kind of M-PLGA-TPGS and preparation method thereof and application | |
| Chen et al. | Amphiphilic poly (ethylene glycol)-b-poly (ethylene brassylate) copolymers: One-pot synthesis, self-assembly, and controlled drug release | |
| Fu et al. | Synthesis and characterization of PEG-based ether− anhydride terpolymers: novel polymers for controlled drug delivery | |
| Li et al. | Synthesis and characterization of amphiphilic block polymer poly (ethylene glycol)-poly (propylene carbonate)-poly (ethylene glycol) for drug delivery | |
| WO2013097152A1 (en) | Ph-sensitive hyaluronic acid derivative and use thereof | |
| Akram et al. | Sustained release of hydrophilic drug from polyphosphazenes/poly (methyl methacrylate) based microspheres and their degradation study | |
| Ramesh et al. | Synthesis of cyclodextrin-derived star poly (N-vinylpyrrolidone)/poly (lactic-co-glycolide) supramolecular micelles via host-guest interaction for delivery of doxorubicin | |
| US20050043481A1 (en) | Material consisting of at least a biodegradable polymer and cyclodextrins |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20141224 |
|
| RJ01 | Rejection of invention patent application after publication |