CN101333295B - Biodegradable high molecular nanometer particles, special polymer thereof and preparation method thereof - Google Patents
Biodegradable high molecular nanometer particles, special polymer thereof and preparation method thereof Download PDFInfo
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Abstract
本发明公开了生物可降解高分子纳米粒子及其专用聚合物和它们的制备方法。本发明所提供的聚(乙交酯/丙交酯)—聚乙二醇—聚(乙交酯/丙交酯)聚合物，其结构式如式I所示，m1、m2为10—80的整数，n1、n2为10—90的整数；m＝m1+m2，n＝n1+n2；m/n＝10/90～80/20；p＝0～454的整数；(m+n)∶p＝100∶0～400。本发明PLGE纳米粒子在制备方法中不使用乳化剂，具有工艺简单、流程短、利于大规模生产的特点；PLGE纳米粒子具有纯度高、生物可降解、良好的药物通透性、生物相容性和生物安全性；PLGE纳米粒子可以干燥成粉末、又很容易在水中分散、不发生团聚，具有优良的保存和使用性能，可满足各种生物医学应用的需要。-[(1/2GA)m1(1/2LA)n1]-b-[(CH2CH2O)p]-b-[(1/2GA)m2(1/2LA)n2]-(式1)The invention discloses biodegradable macromolecular nanoparticles, special polymers and their preparation methods. The poly(glycolide/lactide)-polyethylene glycol-poly(glycolide/lactide) polymer provided by the present invention has a structural formula as shown in formula I, and m1 and m2 are 10-80 Integer, n1, n2 are the integer of 10-90; m=m1+m2, n=n1+n2; m/n=10/90～80/20; p=0～454 integer; (m+n): p=100:0~400. The PLGE nanoparticle of the present invention does not use an emulsifier in the preparation method, and has the characteristics of simple process, short flow process and favorable large-scale production; the PLGE nanoparticle has high purity, biodegradability, good drug permeability and biocompatibility And biological safety; PLGE nanoparticles can be dried into powder, easily dispersed in water without agglomeration, have excellent preservation and use performance, and can meet the needs of various biomedical applications. -[(1/2GA) m1 (1/2LA) n1 ]-b-[(CH 2 CH 2 O) p ]-b-[(1/2GA) m2 (1/2LA) n2 ]-(Formula 1)
Description
Technical field
The present invention relates to Biodegradable high-molecular nanoparticle, specialty polymer and their preparation method that a class has multiple pattern.
Background technology
Nanoparticle generally is meant the particle of granular size in 1～100nm scope.Because the size of nanoparticle is especially little, specific surface is big especially, therefore nanoparticle has peculiar physicalies such as the unexistent small-size effect of general material, surface effects, volume effect, quantum size effect, macro quanta tunnel effect, and the peculiar property that obviously is different from general body material and individual molecule.For example aspect biomedical applications, owing to nanoparticle has than the better physical stability of general microballoon, so the comparable general microball preparation of nanometer formulation has better anti-heat sterilization and stability in storage; Because nanoparticle belongs to colloid system, thus during clinical application nanometer formulation with regard to the easier administration of comparable suspension type microball preparation; Again since little, the surface energy of nano particle diameter big, be easy to locate to be detained at mucous membrane, cornea etc., so nanometer formulation be more conducive to medicine absorption, bioavailability of medicament is improved.In addition,, can be absorbed by the MPS system and arrive liver, spleen and marrow, reach the effect of passive target administration by the skeleton type sustained release preparation that nanoparticle is made; And can reach the initiatively purpose of target administration by nanoparticle surface is modified, thereby change medicine to biomembranous perviousness, help that drug transdermal absorbs and cell in the target transmission.
Nanoparticle can be made by materials with different properties, comprising metal, metallic compound, micromolecular carbon material, inorganic materials, natural and synthetic macromolecular material, and small molecules and the molecular matrix material of high score or the like.The material of nanoparticle not only is directly connected to the final adaptable field of nanoparticle, also is directly connected to nanoparticle suitable preparation method and technology simultaneously.The nanoparticle of unlike material generally needs to prepare with diverse ways, and the key of preparation nanoparticle is size, acquisition narrower particle size distribution and the uniform nanoparticle of size of particles of control nanoparticle, and the agglomeration that reduces or eliminates nanoparticle, this is to guaranteeing nanoparticle when the bio-medical preparation that validity, security and the stability of preparation have significant effects especially.
Three kinds of total the be divided into mechanical crushing method of nanometer particle process method, physics dispersion method and chemical synthesiss, and according to the base material difference of preparation nanoparticle, can be divided into the small molecule material again and be solid phase method, the vapor phase process of base material and comprise the precipitator method, sol-gel processing and comprise the liquid phase method of electrolytic process; And be the self aggregation method of the solvent evaporates of base material and method for extracting, nano-precipitation method, salting-out process, supercutical fluid method, segmented copolymer with the high molecular polymer, and the nanoparticle preparation method who prepares polymer nano-particle by monomer polymerization.The method that with the small molecule material is the substrate preparation nanoparticle generally requires preparation condition very high, nanoparticle also very harsh to technical equipment.And by the control to method complete processing such as sol-gel processing, the precipitator method, evaporating solvent pyrolysis method, oxidation reduction process, solvent-thermal method, spray method, emulsion method and radiation chemistry synthesis method and processing conditions, can obtain the nanoparticle that hollow vesica shape nanoparticle, solid ball shape nanoparticle, rod-like nano particle, flake nano particle, tubular nanometer particle, micellelike nanoparticle, wire nanoparticle or the like have the different shape structure, thereby supply the application of different field such as electronics, optics, chemical industry, pottery, biological medicine.For example at biomedical sector, utilize the nanoparticle granularity little, can penetrate physical barriers in tumour and the various body effectively and reach specific position, finally again can be by the performance of the macrophage phagocytic of reticuloendothelial systems such as liver, spleen, marrow, nanoparticle has become the carrier of important new target administration system, makes the treatment to chronic diseases such as cancers reach tangible high curative effect; Others nanoparticle at biomedicine field also has good prospects for application.
The Biodegradable high-molecular nanoparticle is as the newcomer of nanoparticle, because can be because acid under the environment that has water to exist, alkali or enzyme, the promotion of biological substances such as microorganism and accelerated degradation, molecular rupture, eventual degradation becomes monomer or small molecules, thereby or absorbed by body or excreted by metabolism, can avoid thus gathering in vivo, become foreign matter, the possibility that works the mischief, therefore not only can realize the medicine constant release that non-biodegradation nanoparticle institute can not realization, and can avoid the non-biodegradation nanoparticle to retain existing in vivo potential biological safety and biocompatibility hidden danger for a long time, have even more important purposes at biomedical sector.
In view of the performance of nanoparticle and possible application except outside the Pass having with the material of nanoparticle and size, also the pattern with nanoparticle has confidential relation.For example, because the non-nano spherical particle under the equal volume has bigger specific surface than nano spherical particle, and along with length-to-diameter ratio (particle length/particle dia) the increase specific surface of non-nano spherical particle also increases, but not nano spherical particle has higher surface-sensitive degree than nano spherical particle, therefore can more help particle is carried out finishing.Because the difference of the specific surface size of different-shape nano particle, make the different-shape nano particle of same weight have different drug release behaviors, therefore can regulate the drug release behavior of nanoparticle by the pattern of control nanoparticle, make nanoparticle different application be arranged in the drug release field.Again because non-nano spherical particle has tangible anisotropy, can increase medicine and lesions position contact area, can help the utilization ratio etc. of medicine efficient transfer and raising medicine, make it have special application at some medical field.Just be based on of the potential use of non-nano spherical particle at biomedical sector, various non-nano spherical particles, for example rod-like nano particle, wire nanoparticle, Polygons nanoparticle and membranaceous nano-device come out, and are expected to be applied in fields such as cell sensor, clinical medicine and drug delivery systems.
At present, non-nano spherical particle mostly is obtained by metal, metallic compound, micromolecular carbon material or inorganic materials, indivedual non-spherical high molecular nanometer particles also are to be made by polystyrene-polyacrylic acid (PS-b-PAA) or polystyrene-polyoxyethylene glycol abiotic degradable high polymer materials such as (PS-b-PEG), therefore when being used for biomedical sector, not only can not realize the constant release of medicine, but also have great potential source biomolecule security and biocompatibility harm.
Summary of the invention
The objective of the invention is to have Biodegradable high-molecular nanoparticle, specialty polymer and their preparation method of multiple pattern.
Poly-(glycollide/rac-Lactide)-polyoxyethylene glycol provided by the present invention-poly-(glycollide/rac-Lactide) polymkeric substance, its structural formula be suc as formula shown in the I,
-[(1/2GA)
M1(1/2LA)
N1]-b-[(CH
2CH
2O)
p]-b-[(1/2GA)
M2(1/2LA)
N2]-(formula 1)
In the formula: b is expressed as block polymer;
GA is a glycollide
LA is a rac-Lactide
M1, m2 are 10-80 integer, and n1, n2 are 10-90 integer; M=m1+m2, n=n1+n2;
M/n=10/90～80/20; The integer of p=0～454; (m+n): p=100: 0～400.
Preparation method that should poly-(glycollide/rac-Lactide)-polyoxyethylene glycol-poly-(glycollide/rac-Lactide) polymkeric substance is carried out ring-opening polymerization and is prepared by glycollide, rac-Lactide and polyoxyethylene glycol under catalyzer existence and vacuum, heating condition; Wherein, catalyzer is butyl (tetra) titanate or stannous iso caprylate.
Wherein, catalyst levels is 0.01～0.15% of glycollide and a rac-Lactide gross weight; The number-average molecular weight of polyoxyethylene glycol is 200-20000; The mol ratio of glycollide and rac-Lactide is 10/90～80/20, and the total mole number of glycollide and rac-Lactide is 100: 0～400 with the ratio of the mole number of the structural unit of polyoxyethylene glycol.The vacuum tightness of ring-opening polymerization is not higher than 15Pa; Temperature of reaction is 130～180 ℃; Reaction times is 20～70 hours.
Use poly-(glycollide/rac-Lactide)-polyoxyethylene glycol of the present invention-poly-(glycollide/rac-Lactide) polymkeric substance and can obtain the controlled Biodegradable high-molecular nanoparticle of multiple pattern, this also belongs to protection scope of the present invention.
This Biodegradable high-molecular nanometer particle process method, be to gather (glycollide/rac-Lactide)-polyoxyethylene glycol-poly-(glycollide/rac-Lactide) polymer dissolution in water-miscible organic solvent, to form organic phase, then, described organic phase is added drop-wise to aqueous phase, stir, solidify, obtain described Biodegradable high-molecular nanoparticle.
Wherein, water-miscible organic solvent is dioxane, tetrahydrofuran (THF) or acetone, and poly-(glycollide/rac-Lactide)-polyoxyethylene glycol described in the described organic phase-poly-(glycollide/rac-Lactide) polymer concentration is 4～6mg/ml.Water is a water, and perhaps mass concentration is 2～8% ethanol, methyl alcohol, tetrahydrofuran (THF), acetone or the dioxane aqueous solution; Described water volume is 8～30 times of organic phase volume.Stir the solidified temperature and be 20-30 ℃.
The present invention have multiple pattern the Biodegradable high-molecular nanoparticle base material component poly-(lactide/glycolides) (PLGA) and polyoxyethylene glycol (PEG) all have excellent biodegradability and biocompatibility, also all be that various countries food medicine Surveillance Authority (FDA) ratifies can be used for the intravital composition of people, therefore the PLGE nanoparticle can be used in the body and degradation in vivo, not only may realize the constant release of medicine, and can avoid the hidden danger of biological safety and biocompatibility.Because poly-(glycollide/rac-Lactide) is with the hydrophilic polyglycol copolymerization, poly-(glycollide/rac-Lactide) segmental crystallinity is reduced, and the wetting ability of PLGE is improved, so PLGE has excellent biodegradability, excellent drug permeability, biocompatibility and nontoxicity, can satisfy the needs of various biomedical applications.The PLGE nanoparticle of nucleation-shell structure has good stability.The PLGE nanoparticle can be dry powdered, can kept dry; And the wetting ability PEG segment that constitutes the PLGE nanoparticle shell can make the PLGE nanoparticle disperse at an easy rate in water and not reunite.Therefore the PLGE nanoparticle has good preservation and use properties.
PLGE nanoparticle of the present invention does not use emulsifying agent in the preparation method, have the advantages that technology is simple, flow process short, be beneficial to scale operation; The PLGE nanoparticle has purity height, biodegradable, excellent drug permeability, biocompatibility and biological safety; The PLGE nanoparticle can be dried to powder, be easy to disperse in water, do not reunite again, has good preservation and use properties, can satisfy the needs of various biomedical applications.
Description of drawings
Fig. 1 is the biodegradable PLGE nanoparticle photo of various forms.
Embodiment
The present invention gathers (glycollide/rac-Lactide)-polyoxyethylene glycol-poly-(glycollide/rac-Lactide) (PLGA-PEG-PLGA is called for short PLGE) polymkeric substance, when not containing polyoxyethylene glycol (PEG) section, is the multipolymer of glycollide/rac-Lactide; When containing the PEG section, be a triblock copolymer, wherein, the PLGA section is the random copolymers of glycollide and rac-Lactide, the mol ratio of glycollide and rac-Lactide structural unit is 10/90～80/20.The PLGA section is the hydrophobic section of this triblock copolymer PLGE, and the number-average molecular weight scope is 1900-35000; The PEG section is the hydrophilic section of this triblock copolymer PLGE, and number-average molecular weight is 200-20000; In structural unit, PEG segment structure unit ((CH
2CH
2O)-) the ratio of sum and the sum of PLGA section glycollide and rac-Lactide structural unit less than 3:1.
Simply, can explain by following formula:
-[(1/2GA)
m1(1/2LA)
n1]-b-[(CH
2CH
2O)p]-b-[(1/2GA)
m2(1/2LA)
n2]-
In the formula: b is expressed as block polymer;
GA is a glycollide
LA is a rac-Lactide
M1, m2 are 10-80 integer, and n1, n2 are 10-90 integer;
m＝m1+m2，n＝n1+n2；m/n＝10/90～80/20；
The integer of p=0～454; (m+n): p=100: 0～400.
This PLGE adopts single stage method to be prepared: by the directly ring-opening polymerization and preparing under catalyzer existence and vacuum, heating condition of glycollide, L-rac-Lactide and polyoxyethylene glycol, catalyzer is butyl (tetra) titanate or stannous iso caprylate, and catalyst levels is glycollide and rac-Lactide 0.01～0.15% of the gross weight that feeds intake; Polyreaction vacuum tightness is not higher than 15Pa; Temperature of reaction is 130～180 ℃, and the reaction times is 20～70 hours.
Below with specific embodiment the preparation process of this PLGE polymkeric substance is described.
Embodiment 1～12:
Press reacting material ratio shown in the table 1, with glycollide, L-rac-Lactide, polyoxyethylene glycol (PEG), and be glycollide and L-rac-Lactide weight sum 0.01～0.15% catalyzer (butyl (tetra) titanate or stannous iso caprylate) together, in polymerizing pipe, mix, then under the 15Pa vacuum condition in 130～180 ℃ of thermotonuses 10～70 hours, obtain a series of have different parents/hydrophobic segment length and ratio of polymer PLGE-1～PLGE-12.
The preparation of table 1 PLGE polymkeric substance
The molecular weight distribution of above-mentioned PLGE polymkeric substance is between 1.5-2.5.
Embodiment 13～24:
PLGE had not only contained hydrophilic segment (PEG), but also had contained the amphiphilic segmented copolymer of hydrophobic chain segment (PLGA), so the PLGE nanoparticle can adopt the distinctive self-emulsifying of amphiphilic block copolymer-solvent diffusion self-assembling method preparation in the polymer molecule.Concrete preparation method is as follows: at first the PLGE polymer dissolution is formed the PLGE organic phase in water-miscible organic solvent, then the PLGE organic phase is added drop-wise to gradually 20-30 ℃ of the aqueous phases of certain temperature, make organic solvent be diffused into wetting ability PEG segment in the water PLGE molecule naturally then to the interfacial migration enrichment, finally solidify to form with hydrophobicity PLGA segment and be nuclear, be the PLGE nanoparticle with nuclear-shell structure of shell that the particle size range of this nanoparticle is 10-200nm with wetting ability PEG segment.The water-miscible organic solvent that constitutes the PLGE organic phase among the present invention is dioxane, tetrahydrofuran (THF) or acetone, and PLGE concentration is 4～6mg/ml; What constitute water is distilled water, or contains the distilled water solution (mass concentration is 2～8%) of ethanol, methyl alcohol, tetrahydrofuran (THF), acetone or dioxane.
Because hydrophilic segment is coordinated influence with the ratio of hydrophobic segment to the formation generation of self aggregation nanoparticle in the PLGE molecule, therefore can not need change nanometer particle process method, (m/n and (m+n)/p) or chain length and molecular weight (p and PLGE molecular weight) just can adopt above-mentioned self aggregation method to make from ball-type, spheroid shape, stub type, until a series of Biodegradable high-molecular nanoparticles of different-shapes such as line style with wetting ability PEG segmental ratio and only regulate in the PLGE molecule hydrophobicity PLGA segment.
Press the amount shown in the table 2, (PLGE-1～PLGE-12), be dissolved in 4～6 times of organic solvents to amount of polymers [(4～6) X ml] makes the organic phase that concentration is 4～6mg/ml to take by weighing the polymkeric substance of a certain amount of (X mg).Organic solvent can be dioxane, tetrahydrofuran (THF) or acetone.Prepared polymer organic being added drop-wise to mutually lentamente temperature under 180～200rpm slowly stirs and being 25～30 ℃, volume is the aqueous phase of 8～30 times of organic phase volumes, forms polymer emulsion.Water can be a distilled water, or concentration is 2～8% ethanol, methyl alcohol, tetrahydrofuran (THF), acetone or the dioxane aqueous solution.Slowly stir polymer emulsion down at 25～30 ℃, make the organic solvent in the emulsion droplet be diffused into water, obtain being ball (Fig. 1-a), ellipsoid (Fig. 1-b), stub (Fig. 1-c) or line style (the Biodegradable high-molecular nanoparticle of Fig. 1-d) (NP-1～NP-12) after the curing.
The preparation of table 2 PLGE nanoparticle
Claims (9)
1. poly-(glycollide/rac-Lactide)-polyoxyethylene glycol-poly-(glycollide/rac-Lactide) polymkeric substance, its structural formula be suc as formula shown in the I,
-[(1/2GA)
M1(1/2LA)
N1]-b-[(CH
2CH
2O) p]-b-[(1/2GA)
M2(1/2LA)
N2]-(formula 1)
In the formula: b is expressed as block polymer;
GA is a glycollide
LA is a rac-Lactide
M1, m2 are 10-80 integer, and n1, n2 are 10-90 integer; M=m1+m2, n=n1+n2;
M/n=10/90～80/20; The integer of p=0～454; (m+n): p=100: 0～400.
2. the preparation method of described poly-(glycollide/rac-Lactide)-polyoxyethylene glycol of claim 1-poly-(glycollide/rac-Lactide) polymkeric substance is carried out ring-opening polymerization and is prepared by glycollide, rac-Lactide and polyoxyethylene glycol under catalyzer existence and vacuum, heating condition; Wherein, catalyzer is butyl (tetra) titanate or stannous iso caprylate.
3. preparation method according to claim 2 is characterized in that: described catalyst levels is 0.01～0.15% of glycollide and a rac-Lactide gross weight; The number-average molecular weight of described polyoxyethylene glycol is 200-20000; The mol ratio of glycollide and rac-Lactide is 10/90～80/20, and the total mole number of glycollide and rac-Lactide is 100: 0～400 with the ratio of the mole number of the structural unit of polyoxyethylene glycol.
4. according to claim 2 or 3 described preparation methods, it is characterized in that: the vacuum tightness of described ring-opening polymerization is not higher than 15Pa; Temperature of reaction is 130～180 ℃; Reaction times is 20～70 hours.
5. Biodegradable high-molecular nanometer particle process method, be that described poly-(glycollide/rac-Lactide)-polyoxyethylene glycol of claim 1-poly-(glycollide/rac-Lactide) polymer dissolution is formed organic phase in water-miscible organic solvent, then, described organic phase is added drop-wise to aqueous phase, stir, solidify, obtain described Biodegradable high-molecular nanoparticle.
6. preparation method according to claim 5, it is characterized in that: described water-miscible organic solvent is dioxane, tetrahydrofuran (THF) or acetone, and poly-(glycollide/rac-Lactide)-polyoxyethylene glycol described in the described organic phase-poly-(glycollide/rac-Lactide) polymer concentration is 4～6mg/ml.
7. according to claim 5 or 6 described preparation methods, it is characterized in that: described water is a water, and perhaps mass concentration is 2～8% ethanol, methyl alcohol, tetrahydrofuran (THF), acetone or the dioxane aqueous solution; Described water volume is 8～30 times of organic phase volume.
8. preparation method according to claim 5 is characterized in that: stir the solidified temperature and be 20-30 ℃.
9. the Biodegradable high-molecular nanoparticle that obtains of the arbitrary preparation method of claim 5-8.
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