CN109306048A - A kind of preparation method for the PEG-b-PHBV polymer micelle loading resveratrol - Google Patents
A kind of preparation method for the PEG-b-PHBV polymer micelle loading resveratrol Download PDFInfo
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- CN109306048A CN109306048A CN201710626942.4A CN201710626942A CN109306048A CN 109306048 A CN109306048 A CN 109306048A CN 201710626942 A CN201710626942 A CN 201710626942A CN 109306048 A CN109306048 A CN 109306048A
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- peg
- phbv
- resveratrol
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- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 title claims abstract description 54
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 title claims abstract description 54
- 235000021283 resveratrol Nutrition 0.000 title claims abstract description 54
- 229940016667 resveratrol Drugs 0.000 title claims abstract description 54
- 239000000693 micelle Substances 0.000 title claims abstract description 12
- 229920000642 polymer Polymers 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000011068 loading method Methods 0.000 title claims abstract description 7
- 229920000520 poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Polymers 0.000 title claims description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 44
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000000243 solution Substances 0.000 claims abstract description 24
- 239000005057 Hexamethylene diisocyanate Substances 0.000 claims abstract description 17
- UKLDJPRMSDWDSL-UHFFFAOYSA-L [dibutyl(dodecanoyloxy)stannyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCCCCCC UKLDJPRMSDWDSL-UHFFFAOYSA-L 0.000 claims abstract description 16
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 12
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 238000004108 freeze drying Methods 0.000 claims abstract description 8
- 238000004090 dissolution Methods 0.000 claims abstract description 7
- 238000005303 weighing Methods 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 6
- 229920000070 poly-3-hydroxybutyrate Polymers 0.000 claims abstract description 6
- 239000012975 dibutyltin dilaurate Substances 0.000 claims abstract description 4
- 229920001400 block copolymer Polymers 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 11
- 229920001577 copolymer Polymers 0.000 claims description 6
- 238000002242 deionisation method Methods 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005086 pumping Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 230000001681 protective effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- OEGPRYNGFWGMMV-UHFFFAOYSA-N (3,4-dimethoxyphenyl)methanol Chemical compound COC1=CC=C(CO)C=C1OC OEGPRYNGFWGMMV-UHFFFAOYSA-N 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 238000012661 block copolymerization Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 235000013305 food Nutrition 0.000 description 6
- 230000002209 hydrophobic effect Effects 0.000 description 6
- 238000013268 sustained release Methods 0.000 description 6
- 239000012730 sustained-release form Substances 0.000 description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000005611 electricity Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000001338 self-assembly Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 241000219317 Amaranthaceae Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 235000014676 Phragmites communis Nutrition 0.000 description 2
- 241000489523 Veratrum Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000003712 anti-aging effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000011258 core-shell material Substances 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 235000001497 healthy food Nutrition 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000010148 water-pollination Effects 0.000 description 2
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- PYIXHKGTJKCVBJ-UHFFFAOYSA-N Astraciceran Natural products C1OC2=CC(O)=CC=C2CC1C1=CC(OCO2)=C2C=C1OC PYIXHKGTJKCVBJ-UHFFFAOYSA-N 0.000 description 1
- NDVRQFZUJRMKKP-UHFFFAOYSA-N Betavulgarin Natural products O=C1C=2C(OC)=C3OCOC3=CC=2OC=C1C1=CC=CC=C1O NDVRQFZUJRMKKP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000218231 Moraceae Species 0.000 description 1
- 235000008708 Morus alba Nutrition 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- IHPVFYLOGNNZLA-UHFFFAOYSA-N Phytoalexin Natural products COC1=CC=CC=C1C1OC(C=C2C(OCO2)=C2OC)=C2C(=O)C1 IHPVFYLOGNNZLA-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 1
- 241000205407 Polygonum Species 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229920003232 aliphatic polyester Polymers 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000004146 energy storage Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000280 phytoalexin Substances 0.000 description 1
- 150000001857 phytoalexin derivatives Chemical class 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical class C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/48—Polyethers
- C08G18/4833—Polyethers containing oxyethylene units
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/30—Encapsulation of particles, e.g. foodstuff additives
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- 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
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/30—Low-molecular-weight compounds
- C08G18/32—Polyhydroxy compounds; Polyamines; Hydroxyamines
- C08G18/3203—Polyhydroxy compounds
- C08G18/3206—Polyhydroxy compounds aliphatic
-
- 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
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/4009—Two or more macromolecular compounds not provided for in one single group of groups C08G18/42 - C08G18/64
- C08G18/4018—Mixtures of compounds of group C08G18/42 with compounds of group C08G18/48
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- 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
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
- C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
- C08G18/4283—Hydroxycarboxylic acid or ester
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/65—Low-molecular-weight compounds having active hydrogen with high-molecular-weight compounds having active hydrogen
- C08G18/66—Compounds of groups C08G18/42, C08G18/48, or C08G18/52
- C08G18/6633—Compounds of group C08G18/42
- C08G18/6637—Compounds of group C08G18/42 with compounds of group C08G18/32 or polyamines of C08G18/38
- C08G18/664—Compounds of group C08G18/42 with compounds of group C08G18/32 or polyamines of C08G18/38 with compounds of group C08G18/3203
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
- C08G18/72—Polyisocyanates or polyisothiocyanates
- C08G18/73—Polyisocyanates or polyisothiocyanates acyclic
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2230/00—Compositions for preparing biodegradable polymers
Abstract
A kind of preparation method of polyethylene glycol (PEG)-b- poly- (3-hydroxybutyrate ester -3- hydroxyl valerate) (PHBV) polymer micelle for loading resveratrol of present method invention.42~45%PEG chloroform soln is prepared first, sequentially add hexamethylene diisocyanate (HDI) 10~15% and dibutyl tin dilaurate (T-12) 0.10~0.15%, 42~45%PHBV solution is added after reacting 0.5h, 45~60 DEG C of 4~5h of reaction, it air-dries, water mentions, freeze-drying.Then sample and 5~15mg resveratrol is lyophilized in 30~150mg of accurate weighing, and chloroform dissolution is at the uniform velocity added in the polyvinyl alcohol of 60ml0.5~2.0% (PVA) aqueous solution, evaporates solvent, be centrifuged, washes, freeze-drying.This method raw material is simple, and technology is environmentally protective, and method is simply easily existing, is conducive to medical application.
Description
Technical field
The present invention relates to a kind of polyethylene glycol-b- poly- (3-hydroxybutyrate ester -3- hydroxyl valerate) for loading resveratrol
The preparation method of polymer micelle, belongs to field of biomedicine, is applied to Food Science, drug release or medical instruments field.
Background technique
Polymer micelle has been developed in recent years a kind of newtype drug release system, is amphipathic copolymer water-soluble
By the nanoparticle with typical shell-core structure being self-assembly of in liquid, wherein hydrophobic drug can be by hydrophobic mutual
Effect enters micelle inner core, is effectively improved solubility in its water, and hydrophilic block then constitutes micella around micelle inner core
Shell, for stablizing micella.
Poly- (3-hydroxybutyrate ester -3- hydroxyl valerate) (PHBV) is microorganism in carbon source excess, and nitrogen source, phosphorus source lack
When, it is accumulated in the thermoplastic aliphatic polyester that it is used as nutrition in vivo and energy storage substance participates in cell metabolism.Its is excellent
Biocompatibility, slow degradation rate and no acidic catabolite and medical treatment or nutritive value to cell, are used extensively
Make controlled and sustained release carrier, active material is provided and continues controlled release.However, PHBV toughness and hydrophily are poor, it is to limit it
The most challenging key scientific problems and bottleneck difficult point of application.Polyethylene glycol (PEG) is a kind of water soluble polymer, poison
Property low, immunogenicity and antigenicity it is low, be widely used as amphiphilic polymer nanoparticle hydrophilic segment, biodegradable bio-compatible
Property it is good, can be used as polymeric hydrophilic section, form micellar shell, so that micella is come with stability, extend the circulation time of micella.
Resveratrol (Resveratrol, RES) is also known as resvertrol, is a kind of natural diphenylethylene polyphenol substance, main
It is present in the plants such as polygonum cuspidate, black false hellebore, grape, peanut, mulberries.This resveratrol substance is that plant is invaded in external germ
Enter, a kind of phytoalexin that ultraviolet light irradiation etc. generates under the influence of unfavorable factors, shields to plant itself.As one
Kind has the natural non-flavonoid active compound of stilbene class formation, and RES not only has anti-inflammatory, antithrombotic and other effects, but also has good
Prevention and cure of cardiovascular disease, strong anti-oxidation and remove free radical effect, by the U.S. " anti-aging canon " be classified as 100 kinds it is most effective
One of anti-aging substance has broad application prospects and develops benefit in industries such as food, nutritional supplement product, cosmetics, medicine
With value.Current very extensive to the research and development of resveratrol in the world, health care product, drug and drinks rich in resveratrol
Related product it is very much, the bioactivity of resveratrol has obtained basic approval in the world.
But as a kind of natural Active components of food, resveratrol has active phenolic hydroxyl structure, crystal form mistake
Greatly, water-soluble lower (only 2.68mgL-1), be not easy to be absorbed in vivo, stability is poor, half-life short (8~14min),
Metabolism and excretion are excessively rapid, and bioavilability is low, substantially reduce its inoxidizability and removal free radical effect, seriously affect
The performance of its physiological activity.Therefore, it probes into and improves the water solubility of resveratrol, it is promoted to absorb and improve its biological utilisation
The method of degree is the hot spot and problem of current food nutrition area research.
The present invention is directed to current resveratrol poorly water-soluble, and the disadvantage that internal accretion rate is fast and stability is poor utilizes two
Isocyanates is coupling agent, carries out coupling reaction using the PEG and PHBV of different molecular weight, prepares PEG-b-PHBV block copolymerization
Object.Emulsion solvent evaporation technique constructs the resveratrol block polymer micelle of different PEG molecular weight.This method is by biofacies
The functional character for holding the PHBV and PEG of biodegradable and no acidic metabolin is applied to the loading and stabilisation of resveratrol, opens
Resveratrol-PEG-b-PHBV block the spansule that send out long-acting stable, improves the bioavilability of resveratrol.
Summary of the invention
The present invention is based on PEG/PHBV to develop a kind of biodegradable bio-compatible that can load resveratrol, controllable sustained-release
Micellar structure, PHBV gradually resolve into hydroxybutyric acid in vivo, and final metabolite is water and carbon dioxide, can be used as medical
The auxiliary material of the ejection preparations such as operation suture thread, injection microcapsules and microballoon；PEG is that the only a few through FDA approval can be used as body
One of the polymer of interior injection, PEG-b-PHBV is fabulous as polymer micelle vector safety.
The present invention using with good biocompatibility and biological degradability PHBV and PEG as matrix, utilize hexa-methylene
Diisocyanate (HDI) is coupling agent, and organotin is catalyst, has terminal hydroxy group using PHBV chain end, and PEG molecule also has
Terminal hydroxy group is easy to react with hydroxyl, generation-NH-CO- by-NCO group, and PEG and PHBV coupling is got up, and is catalyzed in T-12
Under prepare the PEG-b-PHBV block copolymer of different molecular weight (400,2000,4000,8000,20000).Emulsification-solvent steams
Hair method constructs the resveratrol block copolymerization micella of different PEG molecular weight, and in aqueous solution, PHBV segments aggregate forms micella
Hydrophobic inner core, package resveratrol enter microballoon, and PEG then forms the shell of micella, and hydrophily can reduce reticular endothelium system
Uniting, to make microballoon, circulation time is greatly prolonged in vivo for the intake of microballoon, it is easier to and reach lesion tissue and plays drug effect,
It can achieve the purpose that self assembly in aqueous solution prepares carrier.Drug becomes drug-carrying nanometer particle by high molecular material load simultaneously
The hypotoxicity that there is son naked medicine cannot compare, this is to increase the dosage of drug in later use without causing toxicity
Reaction provides foundation.For aliphatic HDI compared with aromatic series toluene di-isocyanate(TDI) (TDI), strand is submissive, not will increase production
The rigidity of object will not generate the product-aromatic amine being harmful to the human body in degradation process.Therefore, which can be effectively
Improve resveratrol bioactivity and water solubility, preparation process is simple, and reaction condition is mild, can for develop New Generation of Intelligent,
Efficient drug-loading system provides beneficial technology and theoretical reference.
The purpose of the present invention is realized by following technical formula:
It is a kind of by coupling method construct PEG-b-PHBV block copolymer, by the gross mass of the system be 100% in terms of,
Wherein each component and mass percent are as follows: poly- (3-hydroxybutyrate ester -3- hydroxyl valerate) (PHBV) 42~45%；Poly- second two
Alcohol (PEG) 42~45%；Hexamethylene diisocyanate (HDI) 10~15%；Dibutyl tin dilaurate (T-12) 0.10~
0.15%.
Resveratrol block copolymerization micella of the present invention the preparation method is as follows:
A) PEG of different molecular weight is dissolved in wiring solution-forming in chloroform；The chloroform soln of PHBV is prepared simultaneously；
B) HDI and T-12 are sequentially added into PEG solution；
C) PHBV solution is added in PEG solution after reacting 0.5h, is stirred to react 4~5h, reaction temperature controls 45~
60℃；
D) reaction solution is poured out after reaction, dries 48h at room temperature thoroughly to remove solvent；
E) products therefrom is extracted for 24 hours in Soxhlet extractor with water, removes the PEG not reacted with PHBV, obtained powder
End freeze-drying, as block copolymer.
F) emulsification-evaporation method is used.30~150mg of accurate weighing block copolymer and 5~15mg resveratrol sample
Product are added appropriate chloroform dissolution, are at the uniform velocity added in 0.5~2.0% polyvinyl alcohol of 60ml (PVA) aqueous solution dropwise, in
Magnetic stirrer over night at room temperature.Solvent is evaporated, 12000r/min is centrifuged 10min, and deionization is washed 2 times, is freeze-dried to obtain micella
Powder.
Raw material used in the method for the present invention are simple and easy to get, and PHBV and PEG are full biology drops common currently on the market
Solve plastics, it is easy to buy.PHBV is provided by Hangzhou Tian An Biological Co., Ltd., and PEG is by Tianjin great Mao chemical reagent factory
Purchase.Resveratrol, 98%, it is provided by Suo Laibao Biotechnology Co., Ltd；Polyvinyl alcohol (PVA), 87-89% degree of hydrolysis,
It is bought by Sigma-Aldrich company.HDI, T-12 belong to Aladdin reagent.
Compared with the domestic and international prior art, the beneficial effects of the present invention are:
(1) RES micelle administration system is prepared using PEG-b-PHBV copolymer, both at home and abroad there is not yet document report, technology
It is environmentally protective, and method is simply easy to accomplish, is conducive to medical application.
(2) hydrophobic drug is wrapped up using PEG-b-PHBV, the micella particle of preparation is by hydrophobic poly butyric ester-
Hydroxyl valerate forms kernel, and hydrophilic polyethylene glycol is shell, with higher for hydrophobic drug to contain rate.White Chenopodiaceae
Reed alcohol belongs to poorly water soluble drugs.Block copolymer can be self-assembly of the micella of core-shell structure in an aqueous medium.
(3) resveratrol is loaded by safe and non-toxic hydrophilic PEG-b-PHBV block copolymerization micella, solves white black false hellebore
Quick release and degradation after alcohol is fed as healthy food raw material reduce activity and influence the sciences problems of health-care effect, to open up
Practical application of the wide resveratrol activity factor in field of food science provides potential application prospect.
It is unique in that:
Carrier of the PEG-b-PHBV for selecting safety fabulous as polymer micelle, passes through the shape of typical shell-core structure
At being loaded to resveratrol, this is the protection and transmitting that polyester base boiomacromolecule is grafted in diet function factor
Another important supplement and development.Resveratrol is loaded by safe and non-toxic hydrophilic PEG-b-PHBV block copolymerization micella, is solved
Resveratrol as quick release and degradation after the feed of healthy food raw material, reduce activity simultaneously influence health-care effect science it is difficult
Topic, provides potential application prospect to widen practical application of the resveratrol activity factor in field of food science.For
Supramolecular system theory is supplemented, fills up both at home and abroad in the blank in PEG-b-PHBV block transmitting carrier field, improves slightly solubility medicine
Object oral administration biaavailability reduces and provides new approaches and new method because medication repeatedly causes the low toxicity in blood to react in vivo,
With very big realistic meaning.
Specific embodiment
Below with reference to embodiment, the present invention is further described, but embodiment is merely to illustrate, and is not intended to limit the model of invention
It encloses.
Embodiment 1:
2.0g PEG 2000 is dissolved in wiring solution-forming in 20ml chloroform, 2.0g PHBV is dissolved in 20ml chloroform
Middle wiring solution-forming.It sequentially adds 600 μ l HDI and 6 μ l T-12 into PEG solution, reacts and PHBV solution is added to PEG after 0.5h
In solution, it is stirred to react 4h, entire reaction process temperature control is at 50 DEG C.Reaction solution is poured out after reaction, is dried at room temperature
48h is thoroughly to remove solvent.Products therefrom is extracted for 24 hours in Soxhlet extractor with water, the PEG not reacted with PHBV is removed,
Obtained powder is block copolymer, recovery rate 64.4%.
Using emulsification-evaporation method accurate weighing 150mg copolymer and 5mg resveratrol, 20ml chloroform is added
Dissolution, is at the uniform velocity added in 60ml 1%PVA aqueous solution, at room temperature magnetic stirrer over night dropwise.Evaporate solvent, 12000r/
Min is centrifuged 10min, and deionization is washed 2 times, and freeze-drying obtains solid powder.Scanning electron microscopic observation to resveratrol itself be in stick
Shape structure, and it is spherical in shape in resveratrol block micella, there is micropore, shows block micella to the package success structure of resveratrol
It builds.External sustained release experiment discovery, micella discharge that resveratrol is very fast, and hereafter release is steady, and resveratrol is loaded into glue in the early stage
Shu Hou, the effect discharged when can achieve one long.
Embodiment 2:
2.0g PEG4000 is dissolved in wiring solution-forming in 20ml chloroform, 2.0g PHBV is dissolved in 20ml chloroform
Middle wiring solution-forming.600 μ l HDI and 6 μ l T-12 are sequentially added into PEG solution；PHBV solution is added to PEG after reaction 0.5h
In solution, it is stirred to react 4h, entire reaction process temperature control is at 50 DEG C.Reaction solution is poured out after reaction, is dried at room temperature
48h is thoroughly to remove solvent, recovery rate 73.4%.By products therefrom in Soxhlet extractor with water extracting for 24 hours, remove not with
The PEG of PHBV reaction, the powder finally obtained is block copolymer.
Resveratrol block copolymerization micella is prepared using emulsification-evaporation method.Accurate weighing 100mg copolymer and 5mg
Resveratrol is added the dissolution of 20ml chloroform, is at the uniform velocity added in 60ml1%PVA aqueous solution dropwise, magnetic force stirs at room temperature
It mixes overnight.Solvent is evaporated, 12000r/min is centrifuged 10min, and deionization is washed 2 times, and freeze-drying obtains solid powder.Scanning electricity
Sem observation to resveratrol itself be in club shaped structure, and it is spherical in shape in resveratrol block micella, show block micella dialogue
The package of veratryl alcohol successfully constructs.External sustained release experiment discovery, micella discharge that resveratrol is very fast, and hereafter release is flat in the early stage
Surely, about 87% resveratrol is released altogether in 15 days, it was demonstrated that after resveratrol is loaded into micella, when can achieve one long
The effect of release.
Embodiment 3:
2.0g PEG8000 is dissolved in wiring solution-forming in 20ml chloroform, 2.0g PHBV is dissolved in 20ml chloroform
Middle wiring solution-forming.600 μ l HDI and 6 μ l T-12 are sequentially added into PEG solution；PHBV solution is added to PEG after reaction 0.5h
In solution, it is stirred to react 4h, entire reaction process temperature control is at 50 DEG C.Reaction solution is poured out after reaction, is dried at room temperature
48h is thoroughly to remove solvent.Products therefrom is proposed into pumping for 24 hours with water in Soxhlet extractor, removes the PEG not reacted with PHBV,
The powder finally obtained is block copolymer, recovery rate 73.4%.
Resveratrol block copolymerization micella is prepared using emulsification-evaporation method.Accurate weighing 50mg copolymer and 5mg are white
Veratryl alcohol is added the dissolution of 20ml chloroform, is at the uniform velocity added in 60ml 1%PVA aqueous solution dropwise, magnetic force stirs at room temperature
It mixes overnight.Solvent is evaporated, 12000r/min is centrifuged 10min, and deionization is washed 2 times, and freeze-drying obtains solid powder.Scanning electricity
Sem observation to resveratrol itself be in club shaped structure, and it is spherical in shape in resveratrol block micella, show block micella dialogue
The package of veratryl alcohol successfully constructs.External sustained release experiment discovery, micella discharge that resveratrol is very fast, and hereafter release is flat in the early stage
Surely, after resveratrol is loaded into micella, the effect that is discharged when can achieve one long.
Embodiment 4:
2.0g PEG400 is dissolved in wiring solution-forming in 20ml chloroform, 2.0g PHBV is dissolved in 20ml chloroform
Wiring solution-forming.600 μ l HDI and 6 μ l T-12 are sequentially added into PEG solution；It is molten that PHBV solution is added to PEG after reaction 0.5h
In liquid, it is stirred to react 4h, entire reaction process temperature control is at 50 DEG C.Reaction solution is poured out after reaction, dries 48h at room temperature
Thoroughly to remove solvent.Products therefrom is proposed into pumping for 24 hours with water in Soxhlet extractor, the PEG not reacted with PHBV is removed, obtains
Powder be block copolymer, recovery rate 77.0%.
Resveratrol block copolymerization micella is prepared using emulsification-evaporation method.Accurate weighing 30mg copolymer and 5mg are white
Veratryl alcohol is added the dissolution of 20ml chloroform, is at the uniform velocity added in 60ml 1%PVA aqueous solution dropwise, magnetic force stirs at room temperature
It mixes overnight.Solvent is evaporated, 12000r/min is centrifuged 10min, and deionization is washed 2 times, and freeze-drying obtains solid powder.Scanning electricity
Sem observation to resveratrol itself be in club shaped structure, and it is spherical in shape in resveratrol block micella, show block micella dialogue
The package of veratryl alcohol successfully constructs.External sustained release experiment discovery, after resveratrol is loaded into micella, micella discharges white Chenopodiaceae in the early stage
Reed alcohol is very fast, and hereafter release is steady, the effect discharged when can achieve one long.
Claims (4)
1. a kind of method for constructing PEG-b-PHBV block copolymer by coupling method, with the gross mass of the system for 100%
Meter, poly- (3-hydroxybutyrate ester -3- hydroxyl valerate) (PHBV) 42~45%；Polyethylene glycol (PEG) 42~45%；Hexa-methylene
Diisocyanate (HDI) 10~15%；Dibutyl tin dilaurate (T-12) 0.10~0.15%.
2. copolymer according to claim 1, which is characterized in that the polymers compositions, weight percent are as follows: 1)
Poly- (3-hydroxybutyrate ester -3- hydroxyl valerate) (PHBV) 42~45%；2) polyethylene glycol (PEG) 42~45%；3) six methylene
Group diisocyanate (HDI) 10~15%；4) dibutyl tin dilaurate (T-12) 0.10~0.15%.
3. a kind of method for preparing block copolymer described in claim 1, comprising the following steps:
A) PEG of different molecular weight is dissolved in wiring solution-forming in chloroform, while prepares the chloroform soln of PHBV；
B) HDI and T-12 are sequentially added into PEG solution；
C) PHBV solution is added in PEG solution after reacting 0.5h, is stirred to react 4~5h, entire reaction process temperature control exists
45~60 DEG C；
D) reaction solution is poured out after reaction, dries 48h at room temperature thoroughly to remove solvent；
E) products therefrom is proposed into pumping for 24 hours with water in Soxhlet extractor, removes the PEG not reacted with PHBV, obtained powder is cold
It is lyophilized dry.
4. a kind of preparation method for the PEG-b-PHBV polymer micelle for loading resveratrol, it is characterised in that:
Using emulsification-evaporation method.30~150mg of accurate weighing block copolymer and 5~15mg resveratrol sample are added
Appropriate chloroform dissolution, is at the uniform velocity added in 0.5~2.0% polyvinyl alcohol of 60ml (PVA) aqueous solution, at room temperature dropwise
Magnetic stirrer over night.Solvent is evaporated, 12000r/min is centrifuged 10min, and deionization is washed 2 times, freeze-drying.
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| CN114085348A (en) * | 2021-11-30 | 2022-02-25 | 张威林 | Block copolymer, preparation method and application thereof |
| CN114085348B (en) * | 2021-11-30 | 2023-03-03 | 张威林 | Block copolymer, preparation method and application thereof |
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