CN106700098A - Preparation method of biodegradable supermolecule polylactic acid microspheres - Google Patents
Preparation method of biodegradable supermolecule polylactic acid microspheres Download PDFInfo
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- CN106700098A CN106700098A CN201611157148.1A CN201611157148A CN106700098A CN 106700098 A CN106700098 A CN 106700098A CN 201611157148 A CN201611157148 A CN 201611157148A CN 106700098 A CN106700098 A CN 106700098A
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- polylactic acid
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- 229920000747 poly(lactic acid) Polymers 0.000 title claims abstract description 73
- 239000004626 polylactic acid Substances 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000004005 microsphere Substances 0.000 title claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000007787 solid Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 6
- 238000001291 vacuum drying Methods 0.000 claims abstract description 4
- 229920001432 poly(L-lactide) Polymers 0.000 claims description 35
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000012986 modification Methods 0.000 claims description 8
- 230000004048 modification Effects 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 238000004062 sedimentation Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical group OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 210000000481 breast Anatomy 0.000 claims 1
- 125000000468 ketone group Chemical group 0.000 claims 1
- 230000002045 lasting effect Effects 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 40
- 229920000642 polymer Polymers 0.000 abstract description 25
- 238000002425 crystallisation Methods 0.000 abstract description 15
- 230000008025 crystallization Effects 0.000 abstract description 14
- 239000007788 liquid Substances 0.000 abstract description 10
- 239000003995 emulsifying agent Substances 0.000 abstract description 6
- 230000001105 regulatory effect Effects 0.000 abstract description 5
- 239000000463 material Substances 0.000 abstract description 4
- 239000002028 Biomass Substances 0.000 abstract description 3
- 238000011068 loading method Methods 0.000 abstract description 3
- 239000002244 precipitate Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 229920002521 macromolecule Polymers 0.000 abstract description 2
- 239000002105 nanoparticle Substances 0.000 abstract description 2
- 238000000975 co-precipitation Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 24
- 230000000052 comparative effect Effects 0.000 description 16
- 239000000243 solution Substances 0.000 description 11
- 238000007306 functionalization reaction Methods 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 210000004899 c-terminal region Anatomy 0.000 description 4
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 4
- 229960001225 rifampicin Drugs 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical compound CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- 238000003808 methanol extraction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- KWXIPEYKZKIAKR-UHFFFAOYSA-N 2-amino-4-hydroxy-6-methylpyrimidine Chemical compound CC1=CC(O)=NC(N)=N1 KWXIPEYKZKIAKR-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 238000000429 assembly Methods 0.000 description 1
- 230000000712 assembly Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 238000000205 computational method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical class O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 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
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
- C08J3/14—Powdering or granulating by precipitation from solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
- C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
-
- 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
- C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
- C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2201/00—Properties
- C08L2201/06—Biodegradable
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2203/00—Applications
- C08L2203/02—Applications for biomedical use
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2205/00—Polymer mixtures characterised by other features
- C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group
- C08L2205/025—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group containing two or more polymers of the same hierarchy C08L, and differing only in parameters such as density, comonomer content, molecular weight, structure
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention relates to the field of biodegradable macromolecule, and aims at providing a preparation method of biodegradable supermolecule polylactic acid microspheres. The method comprises the steps that 2-carbamido-4-[1H]-pyrimidone (UPy) end group modified polylactic acid is dissolved in good solvent, poor solvent is dropwise added under the stirring condition; after stirring continues to be conducted, centrifugal washing is conducted, and solid precipitates are collected; vacuum drying is conducted, and then the biodegradable supermolecule polylactic acid microspheres are obtained. Accordingly, the preparation method is simple and easy to implement, and the feasibility of implementation is high. The morphology of polymer microspheres is regulated through a method of combining liquid-liquid separation and polymer crystallization; meanwhile, the structure and performance are regulated, and the application range is extended. Raw materials of prepared materials all come from biomass renewable resources, can be completely degraded after use, are green and environmentally friendly and have good biocompatibility. Chemical-loading particles are prepared through a chemical and polymer coprecipitation method, use of emulsifier can be effectively avoided, and then the polymer nanoparticles or microspheres have a wider application prospect.
Description
Technical field
The present invention relates to Biodegradable high-molecular field, more particularly to a kind of biodegradable supermolecule polylactic acid microsphere
Preparation method.
Background technology
Nano particle or microballoon have obtained widely grinding as a kind of drug carrier material in the control release field of medicine
Study carefully and apply.Microsphere supported some drawbacks that can overcome existing pharmaceutical preparation, using itself nominal particle size and medicine height
Degree dispersion, improves the water solubility and dissolution rate of insoluble drug, improves the bioavailability of medicine.
The conventional method for preparing polymer micro-nano rice grain or microballoon has spray drying, emulsion solvent volatilization and the side condensed
There is clearly disadvantageous part in method, these methods, the use of such as toxic solvent or auxiliary agent is difficult to be removed completely from microballoon, shadow
Ring the biocompatibility of microballoon, it is difficult to regulate and control size and Size Distribution of microballoon etc..In order to overcome the shortcomings of conventional method, document
On reported the method volatilized using precipitation and solvent and prepared the micro-nano microballoon of Biodegradable polymeric.According to document
(Chen X etc., Biomacromolecules 2005,6,2843-2850) is reported, and the PLA (PLA) of many blocks of vertical structure is molten
Then solution replaces in non-solvent again in good solvent, is prepared for flower pattern and discoidal polymer beads, the particle diameter point of particle
Cloth is more uniform, between tens nanometers to several microns.Paper (Zhou Z etc., Macromol.Mater.Eng.2016,301,
274-278) by changing the type of solvent, the concentration of polymer solution and drying means, petal PLA nanometers is prepared for
Piece, the method can controlled material very well porosity and mechanical performance.
PLA can be prepared based on biomass resource, with many excellent performances, such as biodegradability, bio-compatible
Property and environment friendly.Because the monomer of PLA has enantiomerically, therefore PLA has two kinds of enantiomters, i.e. PLLA
(PLLA) and poly- L-lactic acid (PDLA), wherein PLLA is more common.The fusing point of PLLA is 170 DEG C, and crystalline rate is slower.When
When PLLA and PDLA is blended, Stereocomplex crystallization can be formed, fusing point is up to 230 DEG C, than the homojunction of single PLLA or PDLA
It is brilliant high about 50 DEG C.Additionally, the crystallization of polymer can be regulated and controled to PLA end-functionalizations, so as to improve the hot property and shape of polymer
Looks.Paper (Biela T etc., Macromolecules 2015,48,2994-3004) the end of PLA 2- urea groups -4 [1H] -
Pyrimidone (UPy) or uracil are modified, and the blending of PLLA and PDLA equal proportions is dissolved, methanol extraction with 1-METHYLPYRROLIDONE,
It is prepared for spheric granules.When being modified using UPy both-ends, dissolved with chloroform, methanol extraction obtains fibrous pattern knot
Structure.Therefore, the Stereocomplex crystallization of PLA and end group modification are combined, the micro Nano material of different structure and performance can be obtained.
But, the method for most of tradition precipitations and solvent volatilization can only obtain spheric granules.When drug bearing microsphere is prepared,
Traditional preparation methods need to add emulsifying agent.Paper (Teng etc., J.Appl.Polym.Sci.2015,132,42213-42219)
When the star-like polylactic acid microsphere for loading rifampicin medicine is prepared, 2.5% polyvinyl alcohol is added as emulsifying agent, it is final logical
The method for crossing precipitation and washing removes polyvinyl alcohol emulsifying agent.Paper (Zhang etc., Polym.Bull.2012,68,27-36) exists
When preparing star-like poly- (glycolide-co- lactides) random copolymer micro-sphere of bovine serum albumin loading, polyvinyl alcohol conduct is also used
Emulsifying agent.But the use of emulsifying agent makes it difficult to be removed completely from microballoon, so as to limit the wide of biodegradable particle
General application.
The content of the invention
The technical problem to be solved in the present invention is to overcome deficiency of the prior art, there is provided a kind of biodegradable oversubscription
The preparation method of sub- polylactic acid microsphere.
In order to solve the above technical problems, solution of the invention is：
A kind of preparation method of biodegradable supermolecule polylactic acid microsphere is provided, is by 2- urea groups -4- [1H]-pyrimidone
(UPy) PLA of end group modification is dissolved in good solvent, and poor solvent is added dropwise under agitation；Persistently stirring 24 is small
Shi Hou, centrifuge washing, collection solids of sedimentation；After vacuum drying, biodegradable supermolecule polylactic acid microsphere is obtained；It is described good molten
Agent is any one in dichloromethane, chloroform or tetrahydrofuran；Poor solvent is ethanol or methyl alcohol.
In the present invention, when the PLA of 2- urea groups -4- [1H]-pyrimidone (UPy) end group modification is dissolved in good solvent,
The concentration for making PLA solution is 1mg/mL.
In the present invention, the shared volume fraction in the total consumption of solvent of the poor solvent is 20%~90%.
In the present invention, the drying refers to dry 6h at 60 DEG C.
In the present invention, the molecular forms of the PLA of the 2- urea groups -4- [1H]-pyrimidone (UPy) end group modification are in line
Property or three-arm star-shaped, its concrete structure formula is：
Linear polylactic acid：
Three-arm star-shaped PLA：
In above-mentioned formula,
Wherein, n is 40~890.
In the present invention, the molecular weight of the PLA between 3~64kDa, be PLLA, poly- L-lactic acid or
Both mixtures.
Inventive principle is described：
In solvent displacement, crystallization can induce the formation of different micro-nano package assemblies, the structure of micro-nano assembly
It is relevant with nucleating forms, crystalline rate, crystalline texture.PLA has two kinds of crystal forms, and the ratio of two kinds of crystallizations can be by mixing ratio
Example regulation and control, so the different nucleation rate of available two kinds of crystal forms, crystal growth speed, chain stacked form prepare not similar shape
The biodegradable particle of looks.In addition, when introducing can form the oversubscription subbase group of non-covalent bond in segment, interchain phase can be increased
Interreaction force and chain entanglement degree, so as to change the size and pattern of self assembly particle in solution crystallization.
The present invention prepares PLA microballoons by the method that precipitation and solvent volatilize, during solvent is replaced, by liquid liquid
Be separated the mode being combined with polymer crystallization, can obtain the polylactic acid microsphere of different-shape, and, it is different by controlling
The blending of alloisomerism PLA, it is possible to achieve the transformation between the microballoon of different-shape, is substantially distinguished from tradition and precipitates and molten
The getable spheric granules of agent volatilization preparation method institute.
Compared with prior art, the present invention has advantages below：
(1) PLA microballoons of the present invention are prepared using the method for precipitation and solvent volatilization, simple and easy to apply, exploitativeness
It is high.
(2) present invention regulates and controls the shape of polymer microballoon using the method that liquid liquid phase separation and polymer crystallization are combined
Looks, while regulating and controlling its structure and performance, expand range of application.
(3) present invention constructs supermolecule polymer using the Quadrupolar hydrogen bond of UPy, and Quadrupolar hydrogen bond active force is strong, and regulation and control are not
With the chain entanglement degree of chain topological structure PLA, so as to obtain the PLA microballoons of different-shape.
(3) raw material of the material prepared by the present invention is all from biomass renewable resource, can be degradable after use, green
Colour circle is protected, while having good biocompatibility.
(4) present invention is prepared using the method that medicine and polymer are co-precipitated and carries medicine particle, can effectively avoid emulsification
Agent is used, so that polymer nano granules or microballoon have more is widely applied prospect.
Brief description of the drawings
Fig. 1 is the shape characteristic of PLA particles prepared by embodiment 2.
Fig. 2 is the shape characteristic of PLA particles prepared by embodiment 3.
Fig. 3 is the shape characteristic of PLA particles prepared by embodiment 8.
Fig. 4 is the shape characteristic of PLA particles prepared by embodiment 9.
Fig. 5 is the shape characteristic of PLA particles prepared by comparative example 1.
Fig. 6 is the shape characteristic of PLA particles prepared by comparative example 2.
Fig. 7 is the load medicine release profiles of embodiment 2,3 and the supermolecule PLA particles of comparative example 1 in phosphate buffer.
Specific embodiment
The present invention is described in further detail with specific embodiment below in conjunction with the accompanying drawings.The following examples can make
Professional and technical personnel is more fully understood the present invention, but do not limit the invention in any way.
The present invention is prepared and uses reagent as follows with medicine：L- lactides and D- lactides are purchased from Purao AS；L- third
Lactide and D- the lactides recrystallization purifying in ethyl acetate, it is standby；The purchase of 1,6-HD, trimethylolpropane and stannous octoate
From Sigma-Aldrich companies；1,6- diisocyanate is purchased from Wan Hua chemical companies；2- amino-4-hydroxy -6- methylpyrimidines and
N-methyl pyrrolidones is purchased from J＆K companies.
The structural formula of 2- urea groups -4 [1H] pyrimidone (UPy-NCO) of isocyano end-functionalization of the present invention is：
Prepared by reference literature (Meijer E W etc., Science 1997,278,1601-1604) method, specific steps are such as
Under：2- amino-4-hydroxy -6- methylpyrimidines (10.0g) is added into 500ml there-necked flasks, 0.5h is vacuumized at 65 DEG C, filled
Argon gas is protected, and it is catalyst, wherein HDI moles to add 95.0g hexamethylene diisocyanates and 3.2g N-methyls pyrrolidones
Number is 7 times of 2- amino-4-hydroxy -6- methylpyrimidine molal quantitys, and catalyst content is the 3% of total reactant quality.At 100 DEG C
After reaction 16h, product is dissolved in chloroform, it is 6 to instill volume ratio:1 normal heptane is (common with the mixed liquor of isopropyl ether
700ml), precipitate, filtering.White solid product is placed in 50 DEG C of vacuum drying ovens and dries 10h, it is standby.
C-terminal functionalization linear and three-arm star-shaped PLLA and PDLA reference literature (Pan P etc.,
Cryst.GrowthDes.2016,16,1502-1511) method preparation, design molecular weight is the three terminal hydroxy groups end-blocking of 8kg/mol
Three-arm star-shaped PLLA specific preparation process it is as follows：By 20g L- lactides, 0.335g trimethylolpropanes and 0.12g octanoic acid
Stannous are added in flask after drying, argon gas protection, and 5h is reacted under the conditions of 130 DEG C, obtain PLLA products.The crude product that will be obtained
Dissolved in chloroform, precipitating removing unreacted third in absolute ether and the n-hexane in equal volume precipitating reagent of mixing hands over
Ester, filtering, is dried to obtain polymer.By changing the mass ratio of initiator and lactide, it is prepared for different molecular weight
Polymer.The molecular weight of polymer is by nuclear magnetic resonance hydrogen spectruming determining.Hydroxy-end capped linear and three ends of both-end used herein
The preparation condition and molecular weight of hydroxy-end capped three-arm star-shaped PLLA, PDLA are listed in table 1.Table 1：Hydroxy-end capped linear of both-end and
The preparation condition and molecular weight of three-arm star-shaped PLLA, PDLA of three terminal hydroxy groups end-blocking
Note：In polymer name, 2L, 2D, 3L, 3D represent hydroxy-end capped linear PLL A, PDLA of both-end and three ends respectively
Hydroxy-end capped three-arm star-shaped PLLA, PDLA, suffix numeral represents the molecular weight that polymer is calculated from nuclear-magnetism.
1) preparation of UPy ends functionalization PLLA and PDLA
With reference to (Pan P etc., Cryst.Growth Des.2016,16,1502-1511) method, UPy is further prepared for
The PLLA and PDLA of the linear and three-arm star-shaped of terminal group functional, specific method is：By C-terminal functionalization linear or three
Arm star PLLA or PDLA, the UPy-NCO of isocyano end-functionalization, stannous octoate and toluene are placed in uncommon Dinke pipe, argon
Under gas shielded, reacted 12 hours at 110 DEG C；Reaction removes organic solvent after terminating using Rotary Evaporators, is subsequently adding to two
Dissolved in chloromethanes, filtering.Solvent is volatilized at room temperature, the solid matter for the obtaining as PLLA of UPy ends functionalization or
PDLA.Wherein, the mole of UPy-NCO is the linear or three-arm star-shaped PLA 3 times of C-terminal functionalization, and stannous octoate is accounted for
The 0.6% of gross mass, toluene quality is 30 times of PLLA or PDLA mass.
NMR is tested：Using nuclear magnetic resonance (Bruker companies, 400MHz) test polymer1H NMR spectras, Jin Erji
Calculate its number-average molecular weight (Mn).Test temperature is room temperature, and solvent is deuterochloroform, and chemical shift (δ) is corrected by solvent peak.Molecule
Amount calculation specifications：For PLA, in the hydrogen (δ=4.3ppm) and main chain on the tertiary carbon adjacent by comparing terminal hydroxy group on tertiary carbon
The peak area ratio of hydrogen (δ=5.1ppm) calculates the degree of polymerization and molecular weight.
2) preparation of supermolecule PLA microballoons
Embodiment 1~9
In embodiment 1~9, linear or three-arm star-shaped PLLA, PDLA of UPy terminal group functionals is pressed into certain mass than molten
In the good solvents such as dichloromethane, chloroform, tetrahydrofuran, the concentration for making polymer solution is 1mg/mL.After stirring mixing 2h, by
It is added dropwise in the poor solvents such as ethanol, methyl alcohol, stirs, volume fraction shared by poor solvent after 20%~90%, 4h to drip off.
Then after stirring 24h, centrifuge washing collects solids of sedimentation.After 6h is vacuum dried at 60 DEG C of solids of sedimentation, obtaining biology can drop
The supermolecule PLA microballoons of solution.
In comparative example 1 and 2, with the mixing of linear or three-arm star-shaped PLLA, PDLA of C-terminal functionalization or both
Thing is raw material, and PLA particles are prepared using identical method.PLLA, PDLA proportioning, solvent in embodiment 1~9 and comparative example 1~2
Volume fraction shared by middle poor solvent is listed in Table 2 below.
Morphology characterization：Characterized using field emission scanning electron microscope (FESEM).Dry particles of polylactic acid is sticked to
Observed with 5keV accelerating potentials using CorlzeisD Utral55 types FESEM on conductive carbon paste.
The load medicine and medicament slow release of PLA particles are tested by taking cancer therapy drug rifampin as an example, by the rifampin of 10mg, 100mg
UPy terminal group functionals PLLA, PDLA mixture co-dissolve in dichloromethane, the initial concentration of polymer is 1mg/
mL；After 2h, absolute ethyl alcohol is added dropwise over, stirred；Volume fraction shared by ethanol after 70%, 4h to drip off.After stirring 24h, from
The heart, washing, after drying, obtain biodegradable PLA and carry medicine particle.
The PLA load medicine particles for taking 2.5mg are dissolved in the DMF solvent of 10mL, with ultraviolet-visible light point
Absorbance of the light photometric determination solution at 340nm wavelength, the drugloading rate of particle is calculated based on standard curve.
The enzyme degradation experiment of PLA particles：2.0mg Proteinase Ks, 1.0mg sodium azide and a certain amount of filter paper are wrapped
PLA particles are added into 10mL phosphate buffer solutions (pH=7.4,50mM), and being subsequently placed on 37 DEG C of constant-temperature table delays it
Slow degraded, after certain time interval, PLA pellet frozens is dried, according to the weight loss of PLA particles, so as to calculate degraded
Rate.
Thermal performance test：Tested using DSC, nitrogen atmosphere.Sample with 10 DEG C/min from room temperature to 180 DEG C or
230℃.The computational methods of Thermal Parameter are as follows：Endothermic peak melting for the crystallization of PLLA, PDLA homogeneity between 120 DEG C to 160 DEG C
Melt peak, peak temperature is the fusing point of homogeneity crystallization, and integral area is homogeneity crystallization melting enthalpy (Δ Hm,hc).Between 180 DEG C to 220 DEG C
Endothermic peak is the melting peak of PLLA/PDLA solid compound crystals, and integral area is three-dimensional compound crystal enthalpy (Δ Hm,sc).Solid is multiple
Close the relative fractions (f of crystallizationSC) by formula fSC=Δ Hm,sc/(ΔHm,sc+ΔHm,hc) be calculated.
Table 2 is preparation condition, pattern, particle diameter, drugloading rate, the degraded of PLA particles in embodiment 1~9 and comparative example 1~2
Rate and Thermal Parameter.
Table 2：Preparation condition, pattern, particle diameter, drugloading rate, the degradation rate of PLA particles in embodiment 1~9 and comparative example 1~2
And Thermal Parameter
From table 2 and Fig. 1, in example 2, supermolecule PLA particles are petal pattern.And in comparative example 1
Particle shape looks are irregular, illustrate the presence of oversubscription subbase group and can promote chain entanglement, so as to form fluffy petal-shaped structure.Embodiment
4 can not form petal-shaped structure, not have three-arm star-shaped PLA chain entanglement density mainly due to the chain entanglement density of linear PLA
It is high.When the blending mass ratio of PLLA and PDLA is 50/50 (such as embodiment 3,5 and comparative example 2), spherical characteristic is showed,
Formation mainly due to three-dimensional compound crystal causes crystalline rate to be accelerated, and chain piles up tight, reduces the chi of liquid liquid microphase-separated
It is very little, so as to form the less spheric granules of size.Comparative example 1,2,6, change the type of good solvent and poor solvent and good
Volume fraction shared by solvent, can obtain petal-shaped structure, show that the different choice of good solvent and poor solvent is not interfered with
The formation of grain.
Comparative example 3 and comparative example 2, as shown in Figure 1, the spheroidal particle size of embodiment 3 is larger, surface flatness drop
Low, the presence of mainly UPy supermolecules end group increases chain entanglement, easily forms larger particle.Embodiment 4 shows as sheet
Structure, it is impossible to form petal-shaped structure.The shape characteristic of embodiment 6 shows that the PLA of HMW can also form petal-shaped structure,
But when the result of embodiment 7 shows that the quality such as the PLLA and PDLA of HMW are blended, it is impossible to form spheroidal particle.
As shown in Table 2, the blending ratio of supermolecule PLLA and PDLA is changed in embodiment 8,9, comparative example 2,8,9
Understand, by the mixed proportion for changing supermolecule PLLA and PDLA, it is possible to achieve polymer beads are from petal to spherical morphology
Transformation.The enhancing of Stereocomplex crystallization is illustrated, the accumulation of strand is more tight, while crystalline rate is accelerated, be more easy to
Form spheric granules.
PLA particles have slow release effect to being wrapped in intragranular medicine.Take 2mg load medicine PLA particles and be dispersed in 5mLPBS
In cushioning liquid (pH=7.4,50mM), treat that solution is uniformly dispersed, (molecular cut off is during solution is transferred into bag filter
3500), 10mL PBS cushioning liquid (pH=7.4,50mM) are dialysed.Cushioning liquid outside bag filter is through the regular hour
Interval is changed, while using the Concentration of Rifampicin in ultraviolet specrophotometer test cushioning liquid, and then calculate accumulative releasing
High-volume.Fig. 2 is the drug release patterns of PLA load medicine particles in embodiment 2~3 and comparative example 1.As shown in Figure 2, comparative example
2nd, 3 result, when being intended to 50/50 with PLLA and PDLA blending ratio, Stereocomplex crystallization content raise, polymer and
Effect enhancing between drug molecule, chain piles up more tight, so the drug load of PLA particles gradually increases, release
Speed slows down gradually.Table 3 also illustrate that this result simultaneously, and comparative example 2,3,8,9 understands, as PLLA and PDLA is blended
When ratio is intended to 1/1, the drug load of PLA particles increases to 4.11% from 0.34%, and degradation rate is down to 25% from 41%.
Therefore, the linear or three-arm star-shaped PLA particles of UPy terminal group functionals can be used as the carrier of insoluble drug release, and by regulating and controlling PLA
End group modification and PLA crystal form control carry medicine particle release behavior.
Finally it should be noted that listed above is only specific embodiment of the invention.It is clear that the invention is not restricted to
Above example, can also there is many variations.One of ordinary skill in the art can directly lead from present disclosure
The all deformations for going out or associating, are considered as protection scope of the present invention.
Claims (6)
1. a kind of preparation method of biodegradable supermolecule polylactic acid microsphere, it is characterised in that be by 2- urea groups -4- [1H] -
After the PLA of pyrimidone end group modification is dissolved in good solvent, poor solvent is added dropwise under agitation；Lasting stirring
After 24 hours, centrifuge washing, collection solids of sedimentation；After vacuum drying, biodegradable supermolecule polylactic acid microsphere is obtained；It is described
Good solvent is any one in dichloromethane, chloroform or tetrahydrofuran；Poor solvent is ethanol or methyl alcohol.
2. method according to claim 1, it is characterised in that by the poly- breast of 2- urea groups -4- [1H]-pyrimidone end group modification
When acid is dissolved in good solvent, the concentration for making PLA solution is 1mg/mL.
3. method according to claim 1, it is characterised in that the shared volume in the total consumption of solvent of the poor solvent
Fraction is 20%~90%.
4. method according to claim 1, it is characterised in that the drying refers to dry 6h at 60 DEG C.
5. the method according to Claims 1-4 any one, it is characterised in that 2- urea groups -4- [the 1H]-pyrimidine
The molecular forms of the PLA of ketone end group modification are linear or three-arm star-shaped, and its concrete structure formula is：
Linear polylactic acid：Or
Three-arm star-shaped PLA：
In above-mentioned formula,
Wherein, n is 40~890.
6. method according to claim 5, it is characterised in that the molecular weight of the PLA is between 3~64kDa
The mixture of PLLA, poly- L-lactic acid or both.
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