CN106389386A - 一种用于药物包载与缓释的生物相容性交联微纳米材料及其构建工艺 - Google Patents
一种用于药物包载与缓释的生物相容性交联微纳米材料及其构建工艺 Download PDFInfo
- Publication number
- CN106389386A CN106389386A CN201610819800.5A CN201610819800A CN106389386A CN 106389386 A CN106389386 A CN 106389386A CN 201610819800 A CN201610819800 A CN 201610819800A CN 106389386 A CN106389386 A CN 106389386A
- Authority
- CN
- China
- Prior art keywords
- micro
- nano
- particles
- sustained release
- nano material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 238000004132 cross linking Methods 0.000 title claims abstract description 34
- 229940079593 drug Drugs 0.000 title claims abstract description 27
- 239000002086 nanomaterial Substances 0.000 title claims abstract description 22
- 238000005538 encapsulation Methods 0.000 title claims abstract description 17
- 238000013268 sustained release Methods 0.000 title claims abstract description 14
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 14
- 238000005516 engineering process Methods 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract 4
- 239000002105 nanoparticle Substances 0.000 claims abstract description 42
- 229920000058 polyacrylate Polymers 0.000 claims abstract description 31
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 11
- 229920001661 Chitosan Polymers 0.000 claims abstract description 7
- 239000011159 matrix material Substances 0.000 claims abstract description 3
- 239000011859 microparticle Substances 0.000 claims description 27
- IBFYXTRXDNAPMM-BVTMAQQCSA-N Geniposide Chemical group O([C@@H]1OC=C([C@@H]2[C@H]1C(=CC2)CO)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O IBFYXTRXDNAPMM-BVTMAQQCSA-N 0.000 claims description 17
- IBFYXTRXDNAPMM-FZEIBHLUSA-N Geniposide Natural products COC(=O)C1=CO[C@@H](O[C@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2O)[C@H]2[C@@H]1CC=C2CO IBFYXTRXDNAPMM-FZEIBHLUSA-N 0.000 claims description 17
- VGLLGNISLBPZNL-RBUKDIBWSA-N arborescoside Natural products O=C(OC)C=1[C@@H]2C([C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O3)OC=1)=C(CO)CC2 VGLLGNISLBPZNL-RBUKDIBWSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 238000005119 centrifugation Methods 0.000 claims description 8
- 235000013339 cereals Nutrition 0.000 claims description 4
- 240000007594 Oryza sativa Species 0.000 claims description 2
- 235000007164 Oryza sativa Nutrition 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 235000009566 rice Nutrition 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 12
- 239000012620 biological material Substances 0.000 abstract description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 abstract description 4
- AZKVWQKMDGGDSV-BCMRRPTOSA-N Genipin Chemical compound COC(=O)C1=CO[C@@H](O)[C@@H]2C(CO)=CC[C@H]12 AZKVWQKMDGGDSV-BCMRRPTOSA-N 0.000 abstract description 4
- AZKVWQKMDGGDSV-UHFFFAOYSA-N genipin Natural products COC(=O)C1=COC(O)C2C(CO)=CCC12 AZKVWQKMDGGDSV-UHFFFAOYSA-N 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 230000005855 radiation Effects 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 2
- 239000011248 coating agent Substances 0.000 abstract 1
- 238000000576 coating method Methods 0.000 abstract 1
- 229960004679 doxorubicin Drugs 0.000 abstract 1
- 239000002245 particle Substances 0.000 description 22
- 230000008859 change Effects 0.000 description 14
- 238000002156 mixing Methods 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical group O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000005611 electricity Effects 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000004224 protection Effects 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 230000010148 water-pollination Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000002059 diagnostic imaging Methods 0.000 description 2
- 239000004584 polyacrylic acid Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- XJMPAUZQVRGFRE-SCHFUKFYSA-N Gardenoside Natural products O=C(OC)C=1[C@H]2[C@H]([C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O3)OC=1)[C@@](O)(CO)C=C2 XJMPAUZQVRGFRE-SCHFUKFYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 150000004705 aldimines Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 102000006995 beta-Glucosidase Human genes 0.000 description 1
- 108010047754 beta-Glucosidase Proteins 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- XJMPAUZQVRGFRE-AYDWLWLASA-N methyl (1s,4as,7s,7as)-7-hydroxy-7-(hydroxymethyl)-1-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4a,7a-dihydro-1h-cyclopenta[c]pyran-4-carboxylate Chemical compound O([C@@H]1OC=C([C@@H]2[C@H]1[C@](C=C2)(O)CO)C(=O)OC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O XJMPAUZQVRGFRE-AYDWLWLASA-N 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/20—After-treatment of capsule walls, e.g. hardening
- B01J13/22—Coating
-
- 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
- C08J3/126—Polymer particles coated by polymer, e.g. core shell structures
-
- 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
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/245—Differential crosslinking of one polymer with one crosslinking type, e.g. surface crosslinking
-
- 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
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/246—Intercrosslinking of at least two polymers
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2333/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers
- C08J2333/04—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters
-
- 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
- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
- C08J2405/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Optics & Photonics (AREA)
- Nanotechnology (AREA)
- Biomedical Technology (AREA)
- Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Polymers & Plastics (AREA)
- Inorganic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种可用于药物包载与缓释的生物相容性微纳米材料及其构建工艺。其中所构建的生物材料以聚丙烯酸酯微泡或纳米粒子为基体,包裹材料为壳聚糖,交联剂为京尼平,并且以阿霉素为模型药物,考察了其药物包载和释放的特性;经过该方法构建的微纳米粒材料一定程度上提高了药物的包封率和包载率,并且可以适度地控制药物在体外的释放速度;本发明中的制备工艺步骤简单、条件温和、工艺绿色环保、能耗少、无三废及辐射与噪声等污染,是一种微纳米粒子高生物相容的交联的通用工艺。
Description
技术领域
本发明涉及一种用于药物包载与缓释的生物相容性交联微纳米材料及其构建工艺。
背景技术
表面包裹是一种对微纳米粒子进行功能修饰的重要方法之一。使用合适的材料对对微纳米粒子包裹后,其尺寸、表面带电性、稳定性、膨胀系数等诸多性质与包裹前相比会有不同程度的改变。与此同时,包裹材料能有效的赋予微纳米粒子特定的生物化学的性质,为微纳米材料的功能化修饰提供便利。然而包裹材料的生物相容性将直接影响最终微纳米材料的生物活性,包裹材料的可修饰性决定了微纳米材料的修饰前景,因此寻找生物相容性良好,可修饰性强的包裹材料是首要的条件。
与表面包裹一样,表面交联也是对微纳米粒子修饰的重要途径。与包裹的方法不同的是,经包裹后,微纳米粒子的粒径通常会变大,而交联后其粒径通常会变小。重要的是,材料交联后,其致密性的改变,造成了结构稳定性,亲水性,生物可降解性,毒性等一系列理化活性和生物活性的改变,从而极大地拓宽了其在生物医疗方面等方面的运用。此外,材料的交联程度可以很大程度上影响药物的包载效率和药物释放行为。因此,表面交联是提高微纳米粒子载药效率并使所包载在载体上的药物实现缓释和控释的重要手段之一。
醛胺缩合是一种对带氨基的生物材料常用的修饰方法,其中最常用的醛类交联剂是戊二醛,但戊二醛属于易燃易爆品,对环境和人体健康都有一定的危害与威胁。并且戊二醛交联后的生物材料,在体内降解后会产生含醛基的中间体,会使细胞中的蛋白质变性,从而使材料的生物相容性变差。
发明内容
本发明的目的是为了克服现有技术存在的缺点和不足,而提供一种用于药物包载与缓释的生物相容性交联微纳米材料,具有良好的亲水性、生物相容性、稳定性、机械强度及拉伸强度,并且能保持部分原有的生理活性,有望在生物标记与示踪、医学显像、诊疗一体化等领域得到更广泛的应用,在生命健康与个性化医疗等方面产生良好的经济与社会效益。
本发明的第二个目的是提供一种用于药物包载与缓释的生物相容性交联微纳米材料及其构建工艺,该工艺步骤简单、条件温和、工艺绿色环保、能耗少、无三废及辐射与噪声等污染,分离与提纯工艺操作简便,所得体系稳定易于保存,是一种微纳米粒子高生物相容交联的通用工艺。
为实现本发明的第一个目的,本发明的技术方案是以微纳米粒子为基体,包裹材料为壳聚糖,交联剂为京尼平。
进一步设置是所述的微纳米粒子为聚丙烯酸酯微泡或聚丙烯酸酯纳米粒子。
为实现本发明的第二个目的,本发明的技术方案包括以下步骤:
(1)壳聚糖包裹修饰方法,包含以下步骤:
a 将微纳米粒子的水溶液与0.1~1.0的5%壳聚糖溶液混合 1~3小时,形成壳聚糖包裹的微纳米粒子;
b 离心分离出壳聚糖包裹的微纳米颗粒,用纯水洗涤除去未包裹的壳聚糖;
c 浓集后得壳聚糖包裹的微纳米粒子;
(2)京尼平交联修饰方法,包含以下步骤:
d取壳聚糖包裹的微纳米粒子溶液与0.05~0.5体积比的0.1摩尔每升平溶液混合1~24小时;
e离心分离出交联后的微纳米粒子,用纯水洗涤除去未反应的京尼平;
f浓集后得微纳米材料。
本发明所述用于药物包载与缓释的生物相容性交联微纳米材料及其构建工艺,有效提高微纳米粒子的生物相容性和稳定性,有效提高载药效率并调节药物释放行为,有望在生物标记与示踪、医学显像、诊疗一体化等领域得到更广泛的应用,在生命健康与个性化医疗等方面产生良好的经济与社会效益,该工艺步骤简单、条件温和、工艺绿色环保、能耗少、无三废及辐射与噪声等污染,分离与提纯工艺操作简便,所得体系稳定易于保存,是一种微纳米粒子高生物相容交联的通用工艺。
并且该工艺能有效地调节微纳米材料的粒径,能有效地调节微纳米材料的表面电位,能有效地提高药物包载的效率与缓释速度。
其中,所选用包裹微纳米粒子的壳聚糖来源丰富,是地球上仅次于纤维素的第二大可再生资源,也是自然界中唯一的天然阳离子高分子,具有良好的生物相容性、生物可降解性,并且它还具有抗凝血和抗菌的活性。此外,壳聚糖分子中含有大量的氨基和羟基,微纳米材料经壳聚糖包裹后,其亲水性会相应增强,生物相容性增强,稳定性提高。
京尼平是栀子苷经β-葡萄糖苷酶水解后的产物,是一种优良的天然生物交联剂,可以与蛋白质、胶原、明胶和壳聚糖等交联制作生物材料,如人造骨骼、伤口包扎材料等,其毒性远低于戊二醛和其他常用化学交联剂。此外,京尼平本身具有抗菌、抗炎、抗氧化、保护神经元以及有效控制II型糖尿病等生理活性。与微纳米粒子交联之后,京尼平不仅能增强生物材料的机械强度与拉伸强度,并且能保持部分原有的生理活性(如抗菌活性)。
下面结合说明书附图和具体实施方式对本发明做进一步介绍。
附图说明
图1 不同体积比壳聚糖包裹聚丙烯酸酯纳米粒子粒1至3小时后,聚丙烯酸酯纳米粒子粒径和电位的变化情况;
图2不同体积比壳聚糖包裹聚丙烯酸酯微泡 3小时后,聚丙烯酸酯微泡粒径和电位的变化情况;
图3不同体积比京尼平交联壳聚糖包裹的聚丙烯酸酯纳米粒子1至20小时后,聚丙烯酸酯纳米粒子粒径和电位的变化情况;
图4不同体积比京尼平交联聚糖包裹的聚丙烯酸酯微泡1至20小时后,聚丙烯酸酯微泡粒径和电位的变化情况;
图5 a不同剂量的交联剂将模型药物盐酸阿霉素用包载到聚丙烯酸酯微泡上后的包封率和包载率比较;
图5 b模型药物盐酸阿霉素负载于不同交联程度的聚丙烯酸酯微泡上48小时内的释放曲线。
具体实施方式
下面通过实施例对本发明进行具体的描述,只用于对本发明进行进一步说明,不能理解为对本发明保护范围的限定,该领域的技术工程师可根据上述发明的内容对本发明作出一些非本质的改进和调整。
本发明所采用的制备原料均为商品获得。
实施例1:分别取 4管1毫升聚丙烯酸酯纳米粒子,依次加入0.1, 0.2, 0.4, 0.6毫升5%的壳聚糖溶液,同时混合1小时和3小时后,离心分离出聚丙烯酸酯纳米粒子,并用纯水洗涤未包裹的壳聚糖,浓集后将聚丙烯酸酯纳米粒子重新分散于磷酸盐(PPS)缓冲液中保存。用粒度仪测量交联前后的粒径和电位,结果如附图1所示,包裹后聚丙烯酸酯纳米粒子的粒径和表面电位出现不同程度的改变。
实施例2:分别取 7管1毫升聚丙烯酸酯微泡,依次加入0.05, 0.1, 0.2, 0.4,0.6, 0.8, 1.0毫升5%的壳聚糖溶液,同时混合3小时后,离心分离出微泡,并用纯水洗涤未包裹的壳聚糖,浓集后将聚丙烯酸酯微泡重新分散于磷酸盐(PPS)缓冲液中保存。用颗粒计数仪和粒度仪测量交联前后的粒径和电位,结果如附图2所示包裹后聚丙烯酸酯微泡的粒径和电位出现不同程度的改变。
实施例3:分别取 5管1毫升壳聚糖包裹的聚丙烯酸酯纳米粒子,依次加入10, 50,100, 250,500微升0.1摩尔每升的京尼平溶液,同时混合1小时,3小时候以及20小时后,离心分离出聚丙烯酸酯纳米粒子,并用纯水洗涤未未交联的京尼平,浓集后将聚丙烯酸酯纳米粒子重新分散于磷酸盐(PPS)缓冲液中保存。用粒度仪测量交联前后的粒径和电位,结果如附图3所示,交联后聚丙烯酸酯纳米粒子的粒径和表面电位出现不同程度的改变。
实施例4:分别取4管1毫升壳聚糖包裹的聚丙烯酸酯微泡,依次加入5,10, 25, 50微升0.1摩尔每升的京尼平溶液,同时混合1小时、3小时候以及20小时后,离心分离出聚丙烯酸酯微泡,并用纯水洗涤未未交联的京尼平,浓集后将聚丙烯酸酯微泡重新分散于磷酸盐(PPS)缓冲液中保存。用颗粒计数仪和粒度仪测量交联前后的粒径和电位,结果如附图4所示,交联后聚丙烯酸酯微泡的粒径和电位出现不同程度的改变。
实验例:分别取3管2毫升壳聚糖包裹的聚丙烯酸酯微泡,与 1 mg/L的模型药物阿霉素混合后,依次加入0,40, 400微升0.05摩尔每升的京尼平溶液(依次记为m-0,m-40和m-400),混合24小时后,离心分离出载药聚丙烯酸酯微泡,并用纯水洗涤未未交联的京尼平和未包裹的阿霉素,三者的包封率与载药率如附图5a所示, 随着交联剂京尼平量的增加,药物的包载率和包封率均明显增加;三者的释药结果如附图5b 所示,随着交联剂的增加,药物的释放速度明显减慢。
其中,本发明使用粒度仪检测微纳米粒子交联前后粒径与电位的变化,结果显示微纳米材料包裹壳聚糖后,粒径出现变化,电位明显升高,甚至电位从负电反转为正电,而使用京尼平交联后,微纳米粒子的粒径和电位均出现不同程度的降低,如图1~4所示;使用京尼平交联包载模型药物盐酸阿霉素到微纳米材料中,比较了不同交联剂对药物包载效率的影响,并在药物体外释放的使实验中比较了药物在不同交联度材料中的释放行为,结果显示增加交联剂的量可以有效提高药物的包载效率,如图5a所示,而包载于交联度高的材料中的药物释放过程更为缓慢,如图5b所示。
Claims (4)
1.一种用于药物包载与缓释的生物相容性交联微纳米材料,其特征在于:以微纳米粒子为基体,包裹材料为壳聚糖,交联剂为京尼平。
2.根据权利要求1所述的用于药物包载与缓释的生物相容性交联微纳米材料,其特征在于:所述的微纳米粒子为聚丙烯酸酯微泡或聚丙烯酸酯纳米粒子。
3.一种如权利要求1所述的用于药物包载与缓释的生物相容性交联微纳米材料的构建工艺,其特征在于:包括
(1)壳聚糖包裹修饰方法,包含以下步骤:
a 将微纳米粒子的水溶液与0.1~1.0的5%壳聚糖溶液混合 1~3小时,形成壳聚糖包裹的微纳米粒子;
b 离心分离出壳聚糖包裹的微纳米颗粒,用纯水洗涤除去未包裹的壳聚糖;
c 浓集后得壳聚糖包裹的微纳米粒子;
(2)京尼平交联修饰方法,包含以下步骤:
d取壳聚糖包裹的微纳米粒子溶液与0.05~0.5体积比的0.1摩尔每升平溶液混合1~24小时;
e离心分离出交联后的微纳米粒子,用纯水洗涤除去未反应的京尼平;
f浓集后得微纳米材料。
4.根据权利要求3所述的用于药物包载与缓释的生物相容性交联微纳米材料的构建工艺,其特征在于:所述的微纳米粒子为聚丙烯酸酯微泡或聚丙烯酸酯纳米粒子。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610819800.5A CN106389386A (zh) | 2016-09-13 | 2016-09-13 | 一种用于药物包载与缓释的生物相容性交联微纳米材料及其构建工艺 |
US15/599,710 US20180071226A1 (en) | 2016-09-13 | 2017-05-19 | Biocompatible Cross-Linked Micro-Nano Material Used for Drug Loading and Sustained Release and Construction Method Thereof |
EP17173619.2A EP3292908A1 (en) | 2016-09-13 | 2017-05-31 | Biocompatible cross-linked micro-nano material used for drug loading and sustained release and construction method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610819800.5A CN106389386A (zh) | 2016-09-13 | 2016-09-13 | 一种用于药物包载与缓释的生物相容性交联微纳米材料及其构建工艺 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN106389386A true CN106389386A (zh) | 2017-02-15 |
Family
ID=57999155
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610819800.5A Pending CN106389386A (zh) | 2016-09-13 | 2016-09-13 | 一种用于药物包载与缓释的生物相容性交联微纳米材料及其构建工艺 |
Country Status (3)
Country | Link |
---|---|
US (1) | US20180071226A1 (zh) |
EP (1) | EP3292908A1 (zh) |
CN (1) | CN106389386A (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115380999A (zh) * | 2022-08-12 | 2022-11-25 | 北京东方天合生物技术有限责任公司 | 一种提高反刍动物妊娠率的过瘤胃褪黑素组合物及其制备方法和应用 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114904467B (zh) * | 2021-10-13 | 2023-10-13 | 拓腾华宝(苏州)生物技术有限公司 | 一种柠檬酸二次交联的包水型微胶囊及其制备方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102240268A (zh) * | 2011-05-06 | 2011-11-16 | 河北科技大学 | 生物提取物京尼平交联壳聚糖包覆二苯乙烯类化合物的缓控释微球及其制备方法 |
CN102600506A (zh) * | 2012-03-07 | 2012-07-25 | 中国人民解放军第四军医大学 | Ngf壳聚糖微球-高仿生支架缓释系统及其制备方法 |
CN103495209A (zh) * | 2013-09-26 | 2014-01-08 | 福州大学 | 自发荧光骨修复磁性缓释微球 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9710699D0 (en) * | 1997-05-24 | 1997-07-16 | Danbiosyst Uk | Gastro-retentive controlled release system |
-
2016
- 2016-09-13 CN CN201610819800.5A patent/CN106389386A/zh active Pending
-
2017
- 2017-05-19 US US15/599,710 patent/US20180071226A1/en not_active Abandoned
- 2017-05-31 EP EP17173619.2A patent/EP3292908A1/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102240268A (zh) * | 2011-05-06 | 2011-11-16 | 河北科技大学 | 生物提取物京尼平交联壳聚糖包覆二苯乙烯类化合物的缓控释微球及其制备方法 |
CN102600506A (zh) * | 2012-03-07 | 2012-07-25 | 中国人民解放军第四军医大学 | Ngf壳聚糖微球-高仿生支架缓释系统及其制备方法 |
CN103495209A (zh) * | 2013-09-26 | 2014-01-08 | 福州大学 | 自发荧光骨修复磁性缓释微球 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115380999A (zh) * | 2022-08-12 | 2022-11-25 | 北京东方天合生物技术有限责任公司 | 一种提高反刍动物妊娠率的过瘤胃褪黑素组合物及其制备方法和应用 |
CN115380999B (zh) * | 2022-08-12 | 2023-08-29 | 北京东方天合生物技术有限责任公司 | 一种提高反刍动物妊娠率的过瘤胃褪黑素组合物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
US20180071226A1 (en) | 2018-03-15 |
EP3292908A1 (en) | 2018-03-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Lu et al. | Medical applications based on supramolecular self-assembled materials from tannic acid | |
CN104592702B (zh) | 可自愈合的有机物/无机纳米粒子杂化材料及其制备方法 | |
CN107550921B (zh) | 一种纳米颗粒-高分子可注射复合水凝胶双载药体系及其制备方法 | |
CN110551299A (zh) | 一种自粘附性聚丙烯酰胺复合水凝胶及其制备方法与应用 | |
Aradmehr et al. | A novel biofilm based on lignocellulosic compounds and chitosan modified with silver nanoparticles with multifunctional properties: Synthesis and characterization | |
Liu et al. | Polyvinyl alcohol/carboxymethyl chitosan hydrogel loaded with silver nanoparticles exhibited antibacterial and self-healing properties | |
CN102070786A (zh) | 一种透明质酸-海藻酸钠复合水凝胶及其制备方法 | |
CN109897387A (zh) | 一种改性明胶在水包空气乳液中的应用、多孔凝胶及其制备 | |
CN110845662B (zh) | 一种具有最高临界溶液温度和聚集诱导发光荧光性质的聚合物及制备与应用 | |
CN102895665A (zh) | 一种靶向性石墨烯纳米药物载体的制备方法 | |
CN113956413A (zh) | 一种纳米复合水凝胶的制备方法及其在促糖尿病伤口愈合中的应用 | |
CN103205081A (zh) | 一种温度敏感性壳聚糖基聚电解质复合胶束的制备方法 | |
Ghosh et al. | Synthesis of low molecular weight alginic acid nanoparticles through persulfate treatment as effective drug delivery system to manage drug resistant bacteria | |
CN106389386A (zh) | 一种用于药物包载与缓释的生物相容性交联微纳米材料及其构建工艺 | |
Nath et al. | Multifunctional mussel‐inspired Gelatin and Tannic acid‐based hydrogel with pH‐controllable release of vitamin B12 | |
CN112972696B (zh) | 荧光多肽掺杂金属有机框架纳米材料及制备方法和应用 | |
CN111732729B (zh) | 一种电荷可控的聚合物材料及其制备方法与应用 | |
CN108904466A (zh) | 一种含ZnO的水凝胶珠包封难溶性药物的方法 | |
CN109122678A (zh) | 一种纳米银负载于两亲性生物碳材料的纳米银复合物及其制法和用途 | |
CN114601960B (zh) | 负载pH响应型微载体的抗菌水凝胶及其制备方法和应用 | |
CN109400830A (zh) | 一种pH可解离轻度交联聚合物纳米材料及其制备方法和应用 | |
CN1208373C (zh) | 一种亲水核/亲或疏水壳功能化高分子微球的制备方法及相应的微球产品和应用 | |
CN101361976A (zh) | 一种透明质酸修饰聚氰基丙烯酸烷基酯纳米粒及其制备方法和应用 | |
CN110538139B (zh) | 一种具有电活性可降解的超分子微凝胶/载药超分子微凝胶及其制备方法和应用 | |
CN113866073A (zh) | 用于高效捕获癌细胞的酶敏感纳米材料及制备方法和应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170215 |
|
WD01 | Invention patent application deemed withdrawn after publication |