CN106700098B - The preparation method of biodegradable supermolecule polylactic acid microsphere - Google Patents
The preparation method of biodegradable supermolecule polylactic acid microsphere Download PDFInfo
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- CN106700098B CN106700098B CN201611157148.1A CN201611157148A CN106700098B CN 106700098 B CN106700098 B CN 106700098B CN 201611157148 A CN201611157148 A CN 201611157148A CN 106700098 B CN106700098 B CN 106700098B
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- 239000004626 polylactic acid Substances 0.000 title claims abstract description 29
- 229920000747 poly(lactic acid) Polymers 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000004005 microsphere Substances 0.000 title claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 22
- 230000001376 precipitating effect Effects 0.000 claims abstract description 12
- 238000012986 modification Methods 0.000 claims abstract description 10
- 230000004048 modification Effects 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 6
- 238000001291 vacuum drying Methods 0.000 claims abstract description 4
- 238000013019 agitation Methods 0.000 claims abstract description 3
- 230000002045 lasting effect Effects 0.000 claims abstract 2
- 229920001432 poly(L-lactide) Polymers 0.000 claims description 77
- 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000001035 drying Methods 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
- 238000004090 dissolution Methods 0.000 claims description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 239000006071 cream Substances 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 37
- 239000003814 drug Substances 0.000 abstract description 25
- 229920000642 polymer Polymers 0.000 abstract description 25
- 229940079593 drug Drugs 0.000 abstract description 15
- 238000002425 crystallisation Methods 0.000 abstract description 14
- 230000008025 crystallization Effects 0.000 abstract description 13
- 239000003995 emulsifying agent Substances 0.000 abstract description 7
- 239000008187 granular material Substances 0.000 abstract description 7
- 239000007788 liquid Substances 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 4
- 239000002028 Biomass Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- 230000001276 controlling effect Effects 0.000 abstract description 2
- 239000007791 liquid phase Substances 0.000 abstract description 2
- 238000005191 phase separation Methods 0.000 abstract description 2
- 230000001681 protective effect Effects 0.000 abstract 1
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 73
- 230000000052 comparative effect Effects 0.000 description 16
- 239000000243 solution Substances 0.000 description 10
- 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
- 238000002156 mixing Methods 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 238000007306 functionalization reaction Methods 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
- 238000012360 testing method Methods 0.000 description 4
- KWXIPEYKZKIAKR-UHFFFAOYSA-N 2-amino-4-hydroxy-6-methylpyrimidine Chemical compound CC1=CC(O)=NC(N)=N1 KWXIPEYKZKIAKR-UHFFFAOYSA-N 0.000 description 3
- 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-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
- 150000001875 compounds Chemical class 0.000 description 3
- 229960004756 ethanol Drugs 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 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
- 239000005057 Hexamethylene diisocyanate Substances 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical group [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- 238000009825 accumulation Methods 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 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
- 239000000047 product Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 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
- 208000034530 PLAA-associated neurodevelopmental disease Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 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
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000839 emulsion Substances 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 compound 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
- 238000011068 loading method Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 239000002105 nanoparticle 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
- 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
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 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
- 238000000926 separation method 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
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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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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The present invention relates to Biodegradable high-molecular fields, it is desirable to provide a kind of preparation method of biodegradable supermolecule polylactic acid microsphere.It is that 2- urea groups -4- [1H]-pyrimidone (UPy) end group modification polylactic acid is dissolved in good solvent, poor solvent is added dropwise under agitation；After lasting stirring, centrifuge washing collects solid precipitating；After vacuum drying, biodegradable supermolecule polylactic acid microsphere is obtained.Preparation method is simple by the present invention, and exploitativeness is high.Regulate and control the pattern of polymer microballoon using the method that liquid liquid phase separation and polymer crystallization combine, while regulating and controlling its structure and performance, expands application range.The raw material of prepared material is all from biomass renewable resource, can be degradable after use, environmentally protective, while having good biocompatibility.Medicine particle is carried using the method preparation that drug and polymer are co-precipitated, effectively emulsifier can be avoided to use, so that polymer nano granules or microballoon have more broad application prospect.
Description
Technical field
The present invention relates to Biodegradable high-molecular field, in particular to a kind of biodegradable supermolecule polylactic acid microsphere
Preparation method.
Background technique
Nano particle or microballoon have obtained widely grinding as a kind of drug carrier material in the control release field of drug
Study carefully and applies.The microsphere supported some drawbacks that can overcome existing pharmaceutical preparation, using itself nominal particle size and drug height
Degree dispersion, improves the water solubility and dissolution rate of insoluble drug, improves the bioavailability of drug.
The conventional method for preparing polymer micro-nano rice grain or microballoon has the side of spray drying, emulsion solvent volatilization and cohesion
Method, there are clearly disadvantageous places, such as the use of toxic solvent or auxiliary agent to be difficult to completely remove from microballoon for these methods, 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 micro-nano microballoon of Biodegradable polymeric prepared using the method for precipitating and solvent volatilization.According to document
(Chen X etc., Biomacromolecules 2005,6,2843-2850) report, the polylactic acid (PLA) of the more blocks of vertical structure is molten
Then solution is replaced in non-solvent again in good solvent, be prepared for flower pattern and discoidal polymer beads, the partial size 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 type, the concentration of polymer solution and the drying means of solvent, it is prepared for petal PLA nanometer
Piece, this method can very well controlled material porosity and mechanical performance.
PLA can be prepared based on biomass resource, have many excellent performances, such as biodegradability, bio-compatible
Property and environment friendly.Since the monomer of PLA has enantiomerically, therefore there are two types of enantiomters, i.e. Poly L-lactic acid by PLA
(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 individual PLLA or PDLA
It is brilliant about 50 DEG C high.In addition, the crystallization of polymer can be regulated and controled, to PLA end-functionalization so as to improve the hot property and shape of polymer
Looks.Paper (Biela T etc., Macromolecules 2015,48,2994-3004) is in the end of PLA 2- urea groups -4 [1H] -
Pyrimidone (UPy) or uracil modification, PLLA and PDLA equal proportion is blended, is dissolved with N-Methyl pyrrolidone, methanol extraction,
It is prepared for spheric granules.It when being modified using UPy both-end, is dissolved with chloroform, methanol extraction, obtains the pattern knot of threadiness
Structure.Therefore, the Stereocomplex crystallization by PLA and end group modification combine, the micro Nano material of available different structure and performance.
But most of tradition precipitatings and the method for solvent volatilization can only obtain spheric granules.When preparing drug bearing microsphere,
Traditional preparation methods need that emulsifier is added.Paper (Teng etc., J.Appl.Polym.Sci.2015,132,42213-42219)
When preparation loads the star-like polylactic acid microsphere of rifampicin medicine, it joined 2.5% polyvinyl alcohol as emulsifier, finally lead to
The method for crossing precipitating and washing removes polyvinyl alcohol emulsifier.Paper (Zhang etc., Polym.Bull.2012,68,27-36) exists
Prepare bovine serum albumin loading star-like poly- (glycolide-co- lactide) random copolymer micro-sphere when, also use polyvinyl alcohol as
Emulsifier.But the use of emulsifier makes it difficult to completely remove from microballoon, to limit the wide of biodegradable particle
General application.
Summary of the invention
The technical problem to be solved by the present invention is to overcome deficiency in the prior art, provide 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) polylactic acid 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 collect solid precipitating；After vacuum drying, biodegradable supermolecule polylactic acid microsphere is obtained；It is described good molten
Agent is any one in methylene chloride, chloroform or tetrahydrofuran；Poor solvent is ethyl alcohol or methanol.
In the present invention, when 2- urea groups -4- [1H]-pyrimidone (UPy) end group modification polylactic acid is dissolved in good solvent,
Make the concentration 1mg/mL of PLA solution.
In the present invention, poor solvent volume fraction shared in the total dosage of solvent is 20%~90%.
In the present invention, the drying refers to the dry 6h at 60 DEG C.
In the present invention, the molecular forms of the 2- urea groups -4- [1H]-pyrimidone (UPy) end group modification polylactic acid are in line
Property or three-arm star-shaped, concrete structure formula are as follows:
Linear polylactic acid:
Three-arm star-shaped polylactic acid:
In above-mentioned formula,
Wherein, n is 40~890.
In the present invention, the molecular weight of the polylactic acid between 3~64kDa, be Poly L-lactic acid, poly- L-lactic acid or
The mixture of the two.
Inventive principle description:
In solvent displacement, crystallization can induce the formation of different micro-nano package assemblies, the structure of micro-nano assembly
It is related with nucleating forms, crystalline rate, crystalline texture.There are two types of crystal form, the ratios of two kinds of crystallizations can pass through mixing ratio by PLA
Example regulation, so preparing not similar shape using the different nucleation rate of two kinds of crystal forms, crystal growth rate, chain stacked form
The biodegradable particle of looks.In addition, interchain phase can be increased when the oversubscription subbase group of non-covalent bond can be formed by introducing in segment
Interreaction force and chain entanglement degree, to change the size and pattern of self assembly particle in solution crystallization.
The present invention prepares PLA microballoon by the method for precipitating and solvent volatilization, during solvent displacement, passes through liquid liquid
The mutually mode that separation and polymer crystallization combine, the polylactic acid microsphere of available different-shape, moreover, different by control
The transformation between the microballoon of different-shape may be implemented in the blending of alloisomerism polylactic acid, be substantially distinguished from tradition precipitating and it is molten
The getable spheric granules of agent volatilization preparation method institute.
Compared with prior art, the invention has the following advantages that
(1) method preparation of the PLA microballoon of the present invention using precipitating and solvent volatilization, simple and easy, 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 combine
Looks, while regulating and controlling its structure and performance, expand application range.
(3) present invention constructs supermolecule polymer using the Quadrupolar hydrogen bond of UPy, and Quadrupolar hydrogen bond active force is strong, and regulation is not
With the chain entanglement degree of chain topological structure PLA, to obtain the PLA microballoon 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 carries medicine particle using the method preparation that drug and polymer are co-precipitated, and can effectively avoid emulsifying
Agent uses, so that polymer nano granules or microballoon have more broad application prospect.
Detailed description of the invention
Fig. 1 is the shape characteristic of PLA particle prepared by embodiment 2.
Fig. 2 is the shape characteristic of PLA particle prepared by embodiment 3.
Fig. 3 is the shape characteristic of PLA particle prepared by embodiment 8.
Fig. 4 is the shape characteristic of PLA particle prepared by embodiment 9.
Fig. 5 is the shape characteristic of PLA particle prepared by comparative example 1.
Fig. 6 is the shape characteristic of PLA particle prepared by comparative example 2.
Fig. 7 is the load medicine release profiles of embodiment 2,3 and 1 supermolecule PLA particle of comparative example in phosphate buffer.
Specific embodiment
Present invention is further described in detail with specific embodiment with reference to the accompanying drawing.The following examples can make
The present invention, but do not limit the invention in any way is more fully understood in professional and technical personnel.
The present invention prepares used reagent and drug is as follows: L- lactide and D- lactide are purchased from Purao AS；L- third
Lactide and D- the lactide recrystallization purifying in ethyl acetate, it is spare；1,6-HD, trimethylolpropane and stannous octoate purchase
From Sigma-Aldrich company；1,6- diisocyanate is purchased from Wan Hua chemical company；2- amino-4-hydroxy -6- methylpyrimidine and
N-methyl pyrrolidones is purchased from J&K company.
The structural formula of 2- urea groups -4 [1H] pyrimidone (UPy-NCO) of isocyano end-functionalization of the present invention are as follows:
The preparation of reference literature (Meijer E W etc., Science 1997,278,1601-1604) method, specific steps are such as
Under: 2- amino-4-hydroxy -6- methylpyrimidine (10.0g) is added into 500ml three-necked flask, 0.5h is vacuumized at 65 DEG C, fills
Argon gas protection, it is catalyst that 95.0g hexamethylene diisocyanate and 3.2g N-methyl pyrrolidones, which is added, wherein HDI moles
Number is 7 times of 2- amino-4-hydroxy -6- methylpyrimidine molal quantity, and catalyst content is the 3% of total reactant quality.At 100 DEG C
After reacting 16h, product is dissolved in chloroform, is instilled in the mixed liquor of normal heptane and isopropyl ether that volume ratio is 6:1 (altogether
700ml), it precipitates, filtering.White solid product is placed in 50 DEG C of vacuum drying ovens dry 10h, it is spare.
Functionalized linear and three-arm star-shaped PLLA and the PDLA reference literature of C-terminal (Pan P etc.,
Cryst.GrowthDes.2016,16,1502-1511) method preparation, the three terminal hydroxy groups sealing end that design molecular weight is 8kg/mol
Three-arm star-shaped PLLA specific preparation process is as follows: by 20g L- lactide, 0.335g trimethylolpropane and 0.12g octanoic acid
It is added in flask after stannous is dry, argon gas protection reacts 5h under the conditions of 130 DEG C, obtains PLLA product.The crude product that will be obtained
It is dissolved in chloroform, precipitating removes unreacted third and hands in the precipitating reagent that anhydrous ether and n-hexane mix in equal volume
Ester, filtering, is dried to obtain polymer.By changing the mass ratio of initiator and lactide, it is prepared for that there is 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 sealing end
Note: in polymer name, 2L, 2D, 3L, 3D respectively represent hydroxy-end capped linear PLL A, PDLA of both-end and three ends
Hydroxy-end capped three-arm star-shaped PLLA, PDLA, suffix digital representation polymer is from nuclear-magnetism molecular weight calculated.
1) preparation of the end UPy functionalization PLLA and PDLA
Referring to (Pan P etc., Cryst.Growth Des.2016,16,1502-1511) method, it is further prepared for UPy
The PLLA and PDLA of the linear and three-arm star-shaped of terminal group functional, method particularly includes: C-terminal is functionalized 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；Organic solvent is removed using Rotary Evaporators after reaction, is then added to two
It dissolves, filters in chloromethanes.So that solvent is volatilized at room temperature, obtained solid matter be the functionalized PLLA in the end UPy or
PDLA.Wherein, the mole of UPy-NCO is that C-terminal is functionalized 3 times linear or three-arm star-shaped PLA, and stannous octoate accounts for
The 0.6% of gross mass, toluene quality are 30 times of PLLA or PDLA mass.
NMR test: nuclear magnetic resonance (Bruker company, 400MHz) test polymer is utilized1H NMR spectra, Jin Erji
Calculate its number-average molecular weight (Mn).Test temperature is room temperature, and solvent is deuterated chloroform, and chemical shift (δ) is corrected by solvent peak.Molecule
Measure calculation specifications: for PLA, by comparing on tertiary carbon in the hydrogen (δ=4.3ppm) and main chain on the adjacent tertiary carbon of terminal hydroxy group
The peak area ratio of hydrogen (δ=5.1ppm) calculates the degree of polymerization and molecular weight.
2) preparation of supermolecule PLA microballoon
Examples 1 to 9
In Examples 1 to 9, by linear or three-arm star-shaped PLLA, PDLA of UPy terminal group functional by certain mass than molten
In the good solvents such as methylene chloride, chloroform, tetrahydrofuran, make the concentration 1mg/mL of polymer solution.After being stirred 2h, by
It is added dropwise in the poor solvents such as ethyl alcohol, methanol, stirs, volume fraction shared by poor solvent drips off after being 20%~90%, 4h.
Then after stirring for 24 hours, centrifuge washing collects solid precipitating.Solid is precipitated after being dried in vacuo 6h at 60 DEG C, obtaining biology can drop
The supermolecule PLA microballoon of solution.
In comparative example 1 and 2, with the mixing of functionalized linear or three-arm star-shaped PLLA, PDLA of C-terminal or both
Object is raw material, prepares PLA particle using identical method.PLLA, PDLA proportion, solvent in Examples 1 to 9 and comparative example 1~2
Volume fraction shared by middle poor solvent is listed in Table 2 below.
Morphology characterization: it is characterized using field emission scanning electron microscope (FESEM).Dry particles of polylactic acid is adhered to
It is observed on conductive carbon paste using CorlzeisD Utral55 type FESEM with 5keV acceleration voltage.
The load medicine and medicament slow release of PLA particle are tested by taking anticancer drug rifampin as an example, by the rifampin of 10mg, 100mg
UPy terminal group functional PLLA, PDLA mixture co-dissolve in methylene chloride, the initial concentration of polymer is 1mg/
mL；After 2h, dehydrated alcohol is added dropwise, stirs；Volume fraction shared by ethyl alcohol drips off after being 70%, 4h.After stirring for 24 hours, from
The heart, washing after dry, obtain biodegradable polylactic acid and carry medicine particle.
It takes the PLA of 2.5mg to carry medicine particle to be dissolved in the n,N-Dimethylformamide solvent of 10mL, with ultraviolet-visible light point
Absorbance of the light photometric determination solution at 340nm wavelength calculates the drugloading rate of particle based on standard curve.
The enzyme degradation experiment of PLA particle: it a certain amount of is wrapped 2.0mg Proteinase K, 1.0mg sodium azide and with filter paper
PLA particle is added into 10mL phosphate buffer solution (pH=7.4,50mM), and being subsequently placed on 37 DEG C of constant-temperature table keeps it slow
It is slow to degrade, it is after certain time interval, PLA pellet frozen is dry, according to the weight loss of PLA particle, to calculate degradation
Rate.
Thermal performance test: being tested using DSC, nitrogen atmosphere.Sample with 10 DEG C/min from room temperature to 180 DEG C or
230℃.The calculation method of Thermal Parameter is as follows: the endothermic peak between 120 DEG C to 160 DEG C is the molten of PLLA, PDLA homogeneity crystallization
Melt peak, peak temperature is the fusing point of homogeneity crystallization, and integral area is that homogeneity crystallizes melting enthalpy (Δ Hm,hc).Between 180 DEG C to 220 DEG C
Endothermic peak is the melting peak of PLLA/PDLA solid compound crystal, 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, partial size, the drugloading rate, degradation of PLA particle in Examples 1 to 9 and comparative example 1~2
Rate and Thermal Parameter.
Table 2: preparation condition, pattern, partial size, drugloading rate, the degradation rate of PLA particle in Examples 1 to 9 and comparative example 1~2
And Thermal Parameter
By table 2 and Fig. 1 it is found that in example 2, supermolecule PLA particle is petal pattern.And in comparative example 1
Particle shape looks are irregular, illustrate that the presence of oversubscription subbase group can promote chain entanglement, to form fluffy petal-shaped structure.Embodiment
4 can not form petal-shaped structure, mainly since the chain entanglement density of linear PLA does not have three-arm star-shaped PLA chain entanglement density
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,
Mainly since the formation of three-dimensional compound crystal causes crystalline rate to be accelerated, chain accumulation is close, reduces the ruler of liquid liquid microphase-separated
It is very little, to form the lesser spheric granules of size.Comparative example 1,2,6 changes the type of good solvent and poor solvent and good
Volume fraction shared by solvent can obtain petal-shaped structure, show that the different selections of good solvent and poor solvent will not influence
The formation of grain.
Comparative example 3 and comparative example 2, as shown in Figure 1, the spheroidal particle size of embodiment 3 are larger, surface flatness drop
Low, the presence of mainly UPy supermolecule end group increases chain entanglement, biggish particle easy to form.Embodiment 4 shows as sheet
Structure cannot form petal-shaped structure.The shape characteristic of embodiment 6 shows that the PLA of high molecular weight can also form petal-shaped structure,
But embodiment 7 the result shows that the quality such as PLLA and PDLA of high molecular weight be blended when, spheroidal particle cannot be formed.
As shown in Table 2, the blending ratio of supermolecule PLLA and PDLA, comparative example 2,8,9 are changed in embodiment 8,9
It is found that polymer beads may be implemented from petal to spherical morphology by the mixed proportion for changing supermolecule PLLA and PDLA
Transformation.Illustrate the enhancing of Stereocomplex crystallization, more closely, while crystalline rate is accelerated, and is easier to for the accumulation of strand
Form spheric granules.
PLA particle has slow release effect to intragranular drug is wrapped in.It takes 2mg to carry medicine PLA particle and is dispersed in 5mLPBS
It in buffer solution (pH=7.4,50mM), is uniformly dispersed to solution, solution is transferred in bag filter to (molecular cut off is
3500) it, dialyses to 10mL PBS buffer solution (pH=7.4,50mM).Buffer solution outside bag filter is through the regular hour
Interval is replaced, while using the Concentration of Rifampicin in ultraviolet specrophotometer test buffer solution, and then calculates accumulative release
High-volume.Fig. 2 is the drug release patterns that PLA carries medicine particle in embodiment 2~3 and comparative example 1.As shown in Figure 2, comparative example
2,3 as a result, when being intended to 50/50 with PLLA and PDLA blending ratio, the content of Stereocomplex crystallization increases, polymer and
Effect enhancing between drug molecule, chain is accumulated more closely, so the drug load of PLA particle is gradually increased, release
Rate slows down gradually.Simultaneously table 3 also illustrate this as a result, comparative example 2,3,8,9 it is found that as PLLA and PDLA are blended
When ratio is intended to 1/1, the drug load of PLA particle 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 particle of UPy terminal group functional can be used as the carrier of drug release, and pass through regulation PLA
End group modification and PLA crystal form control carry medicine particle release behavior.
Finally it should be noted that the above enumerated are only specific embodiments of the present invention.It is clear that the invention is not restricted to
Above embodiments can also have many variations.Those skilled in the art can directly lead from present disclosure
Out or all deformations for associating, it is considered as protection scope of the present invention.
Claims (5)
1. a kind of preparation method of biodegradable supermolecule polylactic acid microsphere, which is characterized in that be by 2- urea groups -4- [1H] -
After the polylactic acid of pyrimidone end group modification is dissolved in good solvent, poor solvent is added dropwise under agitation；Lasting stirring
After 24 hours, centrifuge washing collects solid precipitating；After vacuum drying, biodegradable supermolecule polylactic acid microsphere is obtained；It is described
Good solvent is any one in methylene chloride, chloroform or tetrahydrofuran；Poor solvent is ethyl alcohol or methanol；
The molecular forms of the polylactic acid of 2- urea groups -4- [the 1H]-pyrimidone end group modification are linear or three-arm star-shaped, specific
Structural formula are as follows:
Linear polylactic acid:Or
Three-arm star-shaped polylactic acid:
In above-mentioned formula,
Wherein, n is 40~890.
2. the method according to claim 1, wherein by the poly- cream of 2- urea groups -4- [1H]-pyrimidone end group modification
When acid dissolution is in good solvent, make the concentration 1mg/mL of PLA solution.
3. the method according to claim 1, wherein the volume that the poor solvent is shared in the total dosage of solvent
Score is 20%~90%.
4. the method according to claim 1, wherein the drying refers to the dry 6h at 60 DEG C.
5. the method according to claim 1, wherein the molecular weight of the polylactic acid is between 3~64kDa
The mixture of Poly L-lactic acid, poly- L-lactic acid or both.
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