CN107057075A - A kind of preparation method of polyacrylic acid poly (lactic acid-glycolic acid) polycaprolactone dual graft copolymer micelle - Google Patents

A kind of preparation method of polyacrylic acid poly (lactic acid-glycolic acid) polycaprolactone dual graft copolymer micelle Download PDF

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CN107057075A
CN107057075A CN201710376602.0A CN201710376602A CN107057075A CN 107057075 A CN107057075 A CN 107057075A CN 201710376602 A CN201710376602 A CN 201710376602A CN 107057075 A CN107057075 A CN 107057075A
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poly
acid
graft copolymer
polycaprolactone
preparation
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朱国全
申红望
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Shandong University of Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
    • C08G81/027—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G containing polyester or polycarbonate sequences
    • 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
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • 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
    • C08G2230/00—Compositions for preparing biodegradable polymers
    • 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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  • Medicinal Chemistry (AREA)
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Abstract

The present invention discloses a kind of preparation method of polyacrylic acid poly (lactic acid-glycolic acid) polycaprolactone dual graft copolymer micelle, using following methods：1）Polyacrylic acid, hydroxy-end capped poly (lactic acid-glycolic acid) monododecyl ether, hydroxy-end capped polycaprolactone list tridecyl ether, solvent and condensing agent are added in dry reactor, reaction obtains polyacrylic acid poly (lactic acid-glycolic acid) polycaprolactone dual graft copolymer；2）Dual graft copolymer and solvent are added in dry reactor, dissolving obtains copolymer stoste；3）Stoste is added in bag filter, put it into the beaker for filling selective solvent, every displacement in 7 hours once, replaces 3~4 times, is then poured into in graduated volumetric flask, scale is adjusted to selective solvent, obtain object of the present invention.Preparation technology of the present invention is simple, be easy to grasp, and gained object is a kind of new pharmaceutical carrier.

Description

A kind of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle Preparation method
Technical field
The present invention relates to a kind of preparation side of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle Method, belongs to biodegradated polymer materal preparing technical field.
Background technology
Polyacrylic acid is a kind of biomaterial with good biocompatibility and biodegradability, with excellent Hydrophily, in medicine extensive application.It is poly-（D,L）Y（The weight ratio of lactic acid and glycolic is 90/ 10）It is the biomaterial with excellent biocompatibility and biodegradability with polycaprolactone, there is preferable hydrophobicity, Medicine is widely used.Poly (lactic acid-glycolic acid) segment, polycaprolactone segment are grafted to polyacrylic acid strand simultaneously Upper resulting poly acrylic acid-poly y-polycaprolactone dual graft copolymer have it is amphipathic, in selective solvent Micella can be self-assembly of, is a kind of new pharmaceutical carrier, is had broad application prospects in medicine.
The content of the invention
It is an object of the invention to provide a kind of preferable poly acrylic acid-poly y of simple to operate and effect-poly- The preparation method of caprolactone dual graft copolymer micelle.Its technical scheme is：
A kind of preparation method of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle, it is characterised in that： The molecular weight of polyacrylic acid segment is 53000~63000 in copolymer, the molecular weight of poly (lactic acid-glycolic acid) segment for 2300~ 2400, the molecular weight of polycaprolactone segment is 2300~2400；Its preparation method is as follows：
1）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer：Poly- third is added in dry reactor Olefin(e) acid, hydroxy-end capped poly (lactic acid-glycolic acid) monododecyl ether, hydroxy-end capped polycaprolactone list tridecyl ether, solvent and Under condensing agent, inert atmosphere, in 27~33 DEG C of stirring reactions 2~3 days, terminating reaction by filtering, dialysis, was dried, obtains mesh Mark thing；
2）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer stoste：Added in dry reactor Poly acrylic acid-poly y-polycaprolactone dual graft copolymer and solvent, in 48~53 DEG C of 50~60 points of stirring and dissolvings Clock, obtains object；
3）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle：At room temperature, stoste is added In bag filter, put it into 500 milliliters of beakers for filling selective solvent, every displacement in 7 hours once, replace 3~4 times, Solution shows blue light in bag filter, is then poured into in graduated volumetric flask, scale is adjusted to selective solvent, obtain Object.
A kind of preparation method of described poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle, step Rapid 1）In, poly (lactic acid-glycolic acid) monododecyl ether is using poly-（D, Pfansteihl）Glycolic monododecyl ether（Lactic acid and ethanol The weight ratio of acid is 90/10）, the mol ratio of poly (lactic acid-glycolic acid) monododecyl ether and polyacrylic acid is 15~25:1, gather oneself The mol ratio of lactone list tridecyl ether and polyacrylic acid is 15~25:1.
A kind of preparation method of described poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle, step Rapid 1）In, condensing agent is usedN,N’- dicyclohexylcarbodiimide,N,N’- DIC or 3- ethyls -1-（3- bis- First aminopropyl）The mol ratio of carbodiimide, condensing agent and polyacrylic acid is 1.07~1.9:1, solvent uses dimethyl sulfoxide (DMSO), instead It is 5~15 g/100 ml to answer thing solution concentration.
A kind of preparation method of described poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle, step Rapid 2）In, solvent uses dimethyl sulfoxide (DMSO), and original liquid concentration is 1~1.5 mg/ml.
A kind of preparation method of described poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle, step Rapid 3）In, bag filter capacity is 5~10 ml, and bag filter molecular cut off is 3500~4500, and selective solvent is using distillation Water, solution concentration is 0.1~0.4 mg/ml.
Compared with prior art, its advantage is the present invention：
1st, the preparation method of described a kind of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle, is used The means that a kind of polymer is combined with the esterification and dialysis that two kinds of different polymeric monomers are carried out simultaneously are simple to operate, easy In grasp；
2nd, a kind of described poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle is a kind of new medicine Thing carrier.
Embodiment
Embodiment 1
1）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer
15.2 grams of polyacrylic acid are added in dry reactor（Molecular weight is 53000）, 12.2 grams of hydroxy-end capped PLA second Alkyd monododecyl ether（Molecular weight is 2300）With 12.2 grams of hydroxy-end capped polycaprolactone list tridecyl ethers（Molecular weight is 2300）, 396 ml dimethyl sulfoxide (DMSO)s are added, 0.075 gram is addedN,N’Under-dicyclohexylcarbodiimide, inert atmosphere, in 27 DEG C stirring reaction 2 days, terminating reaction by filtering, dialysis, is dried, obtains object；
2）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer stoste
120 milligrams of poly acrylic acid-poly y-polycaprolactone dual graft copolymers, 100 millis are added in dry reactor Dimethyl sulfoxide (DMSO) is risen, in 48 DEG C of stirring and dissolvings 50 minutes, object is obtained；
3）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle
At room temperature, 1 milliliter of poly acrylic acid-poly y-polycaprolactone dual graft copolymer stoste is added into 5 milliliters of capacity Bag filter in（Molecular cut off is 3500）, put it into 500 milliliters of beakers for filling distilled water, replaced every 7 hours Once, replace 3 times, solution shows blue light in bag filter, is then poured into in graduated 10 milliliters of volumetric flasks, with distillation Water is adjusted to scale, obtains object.
Embodiment 2
1）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer
15.4 grams of polyacrylic acid are added in dry reactor（Molecular weight is 55000）, 12.1 grams of hydroxy-end capped PLA second Alkyd monododecyl ether（Molecular weight is 2300）With 12.1 grams of hydroxy-end capped polycaprolactone list tridecyl ethers（Molecular weight is 2300）, 397 ml dimethyl sulfoxide (DMSO)s are added, 0.044 gram is addedN,N’Under-DIC, inert atmosphere, in 30 DEG C stirring reaction 2 days, terminating reaction by filtering, dialysis, is dried, obtains object；
2）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer stoste
140 milligrams of poly acrylic acid-poly y-polycaprolactone dual graft copolymers, 100 millis are added in dry reactor Dimethyl sulfoxide (DMSO) is risen, in 50 DEG C of stirring and dissolvings 55 minutes, object is obtained；
3）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle
At room temperature, 1 milliliter of poly acrylic acid-poly y-polycaprolactone dual graft copolymer stoste is added into 7 milliliters of capacity Bag filter in（Molecular cut off is 4000）, put it into 500 milliliters of beakers for filling distilled water, replaced every 7 hours Once, replace 4 times, solution shows blue light in bag filter, is then poured into in graduated 10 milliliters of volumetric flasks, with distillation Water is adjusted to scale, obtains object.
Embodiment 3
1）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer
17.6 grams of polyacrylic acid are added in dry reactor（Molecular weight is 63000）, 12.5 grams of hydroxy-end capped PLA second Alkyd monododecyl ether（Molecular weight is 2400）With 12.5 grams of hydroxy-end capped polycaprolactone list tridecyl ethers（Molecular weight is 2400）, 426 ml dimethyl sulfoxide (DMSO)s are added, 0.066 gram of 3- ethyls -1- is added（3- dimethylaminopropyls）Carbodiimide, inertia Under atmosphere, in 33 DEG C of stirring reactions 3 days, terminating reaction by filtering, dialysis, was dried, obtains object；
2）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer stoste
150 milligrams of poly acrylic acid-poly y-polycaprolactone dual graft copolymers, 100 millis are added in dry reactor Dimethyl sulfoxide (DMSO) is risen, in 53 DEG C of stirring and dissolvings 60 minutes, object is obtained；
3）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle
At room temperature, 1 milliliter of poly acrylic acid-poly y-polycaprolactone dual graft copolymer stoste is added into 8 milliliters of capacity Bag filter in（Molecular cut off is 4500）, put it into 500 milliliters of beakers for filling distilled water, replaced every 7 hours Once, replace 3 times, solution shows blue light in bag filter, is then poured into in graduated 10 milliliters of volumetric flasks, with distillation Water is adjusted to scale, obtains object.

Claims (5)

1. a kind of preparation method of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle, its feature exists In：The molecular weight of polyacrylic acid segment is 53000~63000 in copolymer, and the molecular weight of poly (lactic acid-glycolic acid) segment is 2300 ~2400, the molecular weight of polycaprolactone segment is 2300~2400；Its preparation method is as follows：
1）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer：Poly- third is added in dry reactor Olefin(e) acid, hydroxy-end capped poly (lactic acid-glycolic acid) monododecyl ether, hydroxy-end capped polycaprolactone list tridecyl ether, solvent and Under condensing agent, inert atmosphere, in 27~33 DEG C of stirring reactions 2~3 days, terminating reaction by filtering, dialysis, was dried, obtains mesh Mark thing；
2）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer stoste：Added in dry reactor Poly acrylic acid-poly y-polycaprolactone dual graft copolymer and solvent, in 48~53 DEG C of 50~60 points of stirring and dissolvings Clock, obtains object；
3）The preparation of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle：At room temperature, stoste is added In bag filter, put it into 500 milliliters of beakers for filling selective solvent, every displacement in 7 hours once, replace 3~4 times, Solution shows blue light in bag filter, is then poured into in graduated volumetric flask, scale is adjusted to selective solvent, obtain Object.
2. a kind of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle according to claim 1 Preparation method, it is characterised in that：Step 1）In, poly (lactic acid-glycolic acid) monododecyl ether is using poly-（D, Pfansteihl）Glycolic list Lauryl ether（The weight ratio of lactic acid and glycolic is 90/10）, poly (lactic acid-glycolic acid) monododecyl ether and polyacrylic acid Mol ratio is 15~25:1, the mol ratio of polycaprolactone list tridecyl ether and polyacrylic acid is 15~25:1.
3. a kind of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle according to claim 1 Preparation method, it is characterised in that：Step 1）In, condensing agent is usedN,N’- dicyclohexylcarbodiimide,N,N’- diisopropyl Carbodiimide or 3- ethyls -1-（3- dimethylaminopropyls）The mol ratio of carbodiimide, condensing agent and polyacrylic acid be 1.07~ 1.9:1, solvent uses dimethyl sulfoxide (DMSO), and reactant solution concentration is 5~15 g/100 ml.
4. a kind of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle according to claim 1 Preparation method, it is characterised in that：Step 2）In, solvent uses dimethyl sulfoxide (DMSO), and original liquid concentration is 1~1.5 mg/ml.
5. a kind of poly acrylic acid-poly y-polycaprolactone dual graft copolymer micelle according to claim 1 Preparation method, it is characterised in that：Step 3）In, bag filter capacity be 5~10 ml, bag filter molecular cut off be 3500~ 4500, selective solvent uses distilled water, and solution concentration is 0.1~0.4 mg/ml.
CN201710376602.0A 2017-05-25 2017-05-25 A kind of preparation method of polyacrylic acid poly (lactic acid-glycolic acid) polycaprolactone dual graft copolymer micelle Withdrawn CN107057075A (en)

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