CN110478332A - A kind of preparation method of novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere - Google Patents
A kind of preparation method of novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere Download PDFInfo
- Publication number
- CN110478332A CN110478332A CN201910863708.2A CN201910863708A CN110478332A CN 110478332 A CN110478332 A CN 110478332A CN 201910863708 A CN201910863708 A CN 201910863708A CN 110478332 A CN110478332 A CN 110478332A
- Authority
- CN
- China
- Prior art keywords
- drug
- preparation
- block copolymer
- polyethylene glycol
- microsphere
- 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
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 239000004005 microsphere Substances 0.000 title claims abstract description 33
- 229920001400 block copolymer Polymers 0.000 title claims abstract description 18
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 17
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 61
- 229940079593 drug Drugs 0.000 claims abstract description 42
- 230000001093 anti-cancer Effects 0.000 claims abstract description 8
- 229920001577 copolymer Polymers 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 17
- 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 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000002474 experimental method Methods 0.000 claims description 9
- 239000013642 negative control Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- 229940009456 adriamycin Drugs 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 238000011156 evaluation Methods 0.000 claims description 6
- 230000012010 growth Effects 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000008367 deionised water Substances 0.000 claims description 5
- 229910021641 deionized water Inorganic materials 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000002835 absorbance Methods 0.000 claims description 4
- 238000004108 freeze drying Methods 0.000 claims description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- 238000006116 polymerization reaction Methods 0.000 claims description 4
- 238000012360 testing method Methods 0.000 claims description 4
- 230000002209 hydrophobic effect Effects 0.000 claims description 3
- 229930192392 Mitomycin Natural products 0.000 claims description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 2
- 229940123237 Taxane Drugs 0.000 claims description 2
- 230000000202 analgesic effect Effects 0.000 claims description 2
- 229940035676 analgesics Drugs 0.000 claims description 2
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 210000002249 digestive system Anatomy 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000004519 grease Substances 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 229960000905 indomethacin Drugs 0.000 claims description 2
- 239000004816 latex Substances 0.000 claims description 2
- 229920000126 latex Polymers 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- 230000002093 peripheral effect Effects 0.000 claims description 2
- 210000002345 respiratory system Anatomy 0.000 claims description 2
- -1 soft red Mycin Chemical compound 0.000 claims description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims 1
- 230000003266 anti-allergic effect Effects 0.000 claims 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims 1
- 229940127093 camptothecin Drugs 0.000 claims 1
- 238000013329 compounding Methods 0.000 claims 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 238000012925 biological evaluation Methods 0.000 abstract 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 32
- 238000000034 method Methods 0.000 description 19
- 230000000694 effects Effects 0.000 description 11
- 239000002077 nanosphere Substances 0.000 description 10
- 229930012538 Paclitaxel Natural products 0.000 description 8
- 229960001592 paclitaxel Drugs 0.000 description 8
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000007334 copolymerization reaction Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000003501 co-culture Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000693 micelle Substances 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004632 polycaprolactone Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 210000003556 vascular endothelial cell Anatomy 0.000 description 2
- XBBVURRQGJPTHH-UHFFFAOYSA-N 2-hydroxyacetic acid;2-hydroxypropanoic acid Chemical compound OCC(O)=O.CC(O)C(O)=O XBBVURRQGJPTHH-UHFFFAOYSA-N 0.000 description 1
- UWSONZCNXUSTKW-UHFFFAOYSA-N 4,5-Dimethylthiazole Chemical compound CC=1N=CSC=1C UWSONZCNXUSTKW-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 229940088529 claritin Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000005076 polymer ester Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of preparation methods of novel polyethylene glycol gamma butyrolactone (PEG-PBL) di-block copolymer nano drug-carrying microsphere.PEG-PBL copolymer nano drug bearing microsphere partial size provided by the invention is small, narrowly distributing, drugloading rate are high, long-acting slow-release can reduce administration number of times.In addition, according to biological evaluation result, it was demonstrated that polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere has excellent biocompatibility and anticancer activity.The preparation method of novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere provided by the invention is simple, is easy to large-scale production, has broad application prospects in medicament slow release field.
Description
Technical field
The invention belongs to polymer drugs to discharge carrier preparation technical field, and in particular to a kind of novel polyethylene glycol γ fourth
The preparation method of lactone di-block copolymer nano drug-carrying microsphere.
Background technique
Nano-medicament carrier refers to the carrier for drug release with nanoscale.It may be implemented using nano-medicament carrier
To carrying for chemotherapeutics, albumen and nucleic acid drug etc..Currently, multiple material is widely used in building nano-medicament carrier
And part has been in commercialization or clinical investigation phase.Amphipathic nature block polymer can be in water from group due to its unique structure
Nanosphere is dressed up, the solubility of dewatering medicament in water can be effectively improved.
Hydrophilic block in amphipathic nature block polymer is mainly polyoxyethylene (PEO) or is polyethylene glycol (PEG) etc., hydrophobic
Block be mainly polylactic acid (PLA), polycaprolactone (PCL), polyglycolide (PGA), poly (lactic acid-glycolic acid) ester (PLGA), in poly- penta
Ester (PVL) and polyaminoacid etc..Examples of such carriers has strong Drug loading capacity, stability is good, circulation time in vivo is long and targeting conveying
The features such as.
Poly- gamma butyrolactone (PBL) be it is a kind of using gamma butyrolactone as monomer ring-opening polymerisation obtain have superior bio compatibility and drop
Solve the polyphosphazene polymer ester material of performance, poly- gamma butyrolactone and poly- γ hydroxybutyric acid (P4HB) there is identical chemical structure,
Poly- γ hydroxybutyric acid passed through U.S. Food and Drug Administration (U.S. Food and Drug Administration,
U.S.FDA) ratify, and be applied to the fields such as operation suture thread and sticking patch.However, so far, only an example is based in γ fourth
Ester ring-opening polymerisation prepares application study (US 7897168B2) of the segmented copolymer as implantation instrument drug releasing controlled coating.Cause
This, researches and develops a kind of novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere, answers in theoretical research and industry
Important meaning and value are all had with aspect.
Summary of the invention
The object of the present invention is to provide a kind of novel polyethylene glycol gamma butyrolactone (PEG-PBL) di-block copolymer nanometers to carry
The preparation method of medicine microballoon, easy to operate, time-saving and efficiency are easy to industrialization.Meanwhile it carrying out cell compatibility evaluation and having resisted
Cancer activity experiment.
The preparation side provided by the invention for preparing novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere
Method is prepared by solvent evaporation method, comprising steps of
(1) polyethylene glycol gamma butyrolactone di-block copolymer, drug and volatile organic solvent are stirred into uniform oil
Phase solution A；
(2) deionized water is added into solution A, after microjet homogenizer is repeatedly homogeneous, obtains homogeneous latex emulsion B；
(3) lotion B stirs volatilization removing organic solvent at room temperature and acquires drug bearing microsphere suspension C；
(4) by suspension C high speed refrigerated centrifuge, it is centrifuged obtained solid freeze-drying, that is, is prepared into the nanometer based on PEG-PBL and carries
Medicine microballoon.
(5) drug release is carried out 7 days at 37 DEG C in the phosphate buffer solution (PBS solution) of pH=7.4, corresponding
Time point takes out dissolution medium, and supplements fresh PBS solution.
(6) L929 cell is cultivated, cell compatibility evaluation is carried out.L929 cell and nanosphere is examined to co-culture using mtt assay
Relative growth rate afterwards, respectively for 24 hours, 48h and 72h, then the absorbance value of measurement bluish violet crystallization first a ceremonial jade-ladle, used in libation passes through formula meter
Calculation obtains cell relative growth rate.
(7) A549 cell is cultivated, anticancer activity experiment is carried out.A549 cell is examined to train altogether with medicament-carrying nano-microsphere using mtt assay
A series of concentration gradient of medicament-carrying nano-microspheres is arranged in relative growth rate after supporting, and drug bearing microsphere is anti-under inspection various concentration
Cancer activity.The absorbance value that first a ceremonial jade-ladle, used in libation is crystallized by measurement bluish violet, is then calculated cell relative growth rate by formula, by
The anticancer activity of this evaluation medicament-carrying nano-microsphere.
In the above method, in the step S1 shown in polyethylene glycol gamma butyrolactone di-block copolymer such as formula (I),
Wherein m is the degree of polymerization, 4≤m≤2000；N is the degree of polymerization, 2≤n≤1000
In the above method, physically trapping hydrophobic drug is low solubility in aqueous solution or under hydrophilic environment in the step S1
Any active medicine, including be not limited to anticancer drug (such as adriamycin, daunorubicin, methotrexate (MTX), mitomycin, camplotheca acuminata
Bases or Taxane family), analgesic or anti-inflammatory drug (such as Indomethacin), medicine for central nervous system, peripheral neverous system medicine
Object, circulatory system drug, medicine for respiratory system, medicine for digestive system, Claritin and hormone medicine.
Cell compatibility: mtt assay is a kind of method for examining cell survival.Block copolymer material is evaluated by MTT experiment
Cell in vitro toxicity, quickly and easily screen bio-medical material[129].Most general cell line in biocompatibility experiment
It is L-929 cell.When being injected intravenously vesicle solution, needs assessment its whether to vascular endothelial cell generate toxicity.Work as vesica
After solution enters blood, what is contacted at first is vascular endothelial cell.Therefore L-929 cell is often selected to evaluate block copolymer material
The cell compatibility of material.
Using the anticancer activity of mtt assay evaluation drug bearing microsphere and free drug.It chooses A549 cell to be tested, paclitaxel carried medicine
Drug concentration is between 0.025~50 μ g/mL in microballoon.
In the above method, organic solvent is methylene chloride, in chloroform, tetrahydrofuran, acetonitrile, ether, acetone in the step (1)
Any one.
In the above method, the concentration of copolymer is 1~50g/L in oily phase in the step (1), and drug concentration is 0.1~10g/
L。
In the above method, mixing speed is 100~2000rpm in the step (1), and mixing time is 10-30 min.
In the above method, grease volume ratio is 0.1~5 in step (2).
In the above method, the chamber pressure in microjet homogenizer described in step (2) is 40MPa~200MPa.
In the above method, the cavity in microjet homogenizer described in step (2) is multiple by two in following three kinds of size cavities
With obtaining: 75 μm, 400 μm and 10mm.
In the above method, the homogeneous number of microjet is 2-5 times in step (2).
In the above method, mixing speed described in step (3) is 100~2000rpm, and mixing time is 5~24 h.
In the above method, it is 15000~25000rpm that step (4) high speed refrigerated centrifuge, which obtains rate, and the time is 8~20min.
In the above method, 10~1000nm of medicament-carrying nano-microsphere partial size described in step (4).
In the above method, in step (5), the bag filter for filling medicament-carrying nano-microsphere solution is put into containing 30mL PBS solution
Centrifuge tube in, then by centrifuge tube be put into water bath with thermostatic control oscillation case in, oscillation rate 100rpm, temperature setting be 37 DEG C.
In the above method, step S6, in S7, Cell relative activity by test sample and negative control OD
The ratio between value calculates:
Relative activity (%)=(ODExperimental group/ODNegative control) × 100%
Beneficial effects of the present invention:
For the present invention using novel PEG-PBL di-block copolymer as pharmaceutical carrier, drug bearing microsphere has excellent bio-compatible
Property, it can get stabilization medicines sustained-release micro-spheres and sustained release performance be adjustable；Using microjet as supplementary means, PEG-PBL load is realized
In the accurate control of following 1000nm and good monodisperse status is presented in medicine microspherulite diameter.
It is evaluated by cell compatibility, it was demonstrated that the in vitro toxicity of blank PEG-PBL nanosphere is smaller, and Cell relative activity exists
80% or more, illustrate that the nanosphere has good biocompatibility.
Passing through inhibiting tumor cell activity experiment, it was demonstrated that the anticancer activity of PEG-PBL medicament-carrying nano-microsphere is preferable, meanwhile, to specific ionization
The anticancer activity of drug, with obvious slow release effect.
Detailed description of the invention
More clearly to describe the embodiment of the present invention or technical solution, brief introduction will be done to attached drawing below, it is illustrated below to be only
The part figure of the embodiment of the present invention, those skilled in the art can obtain other accompanying drawings according to attached drawing is provided.
Fig. 1 is the transmission electron microscope photo of the PEG-PBL drug bearing microsphere for being loaded with adriamycin prepared in the embodiment of the present invention 1.
Fig. 2 is the transmission electron microscope photo of the PEG-PBL drug bearing microsphere for being loaded with taxol prepared in the embodiment of the present invention 3.
Fig. 3 is the PEG-PBL drug bearing microsphere drug release patterns for being loaded with adriamycin prepared in the embodiment of the present invention 3.
Fig. 4 is to evaluate mtt assay by cell compatibility in the embodiment of the present invention 4 to examine the external of blank PEG-PBL nanosphere
Toxicity, by formula calculate nanosphere and cell co-culture for 24 hours, the cell activity histogram that measures after 48h and 72h.
Fig. 5 is to examine the anticancer of various concentration medicament-carrying nano-microsphere living by inhibiting tumor cell activity experiment in the embodiment of the present invention 5
Property, using blank nanosphere and free drug as control.
Specific embodiment
In the following, the present invention will be further described in detail by way of specific embodiments, but this should not be interpreted as to model of the invention
It encloses and is only limitted to example below.Without departing from the idea of the above method of the present invention, according to ordinary skill knowledge
The various replacements or change made with customary means, should be included in the scope of the present invention.
Embodiment 1, the preparation for carrying adriamycin PEG-PBL nanosphere
100mg PEG-PBL (weight average molecular weight 10000, copolymerization ratios 1:1), 20mg adriamycin are weighed, 4mL dichloromethane is added
In alkane, 500rpm stirring 10min dissolves PEG-PBL and drug, then 30mL deionized water is added thereto, in 100MPa pressure
Under, colostric fluid is added into microjet homogenizer, 75 μm and 400 μm of runner processings, and homogeneous 3 times repeatedly are selected.100rpm
Stirring 12h makes solvent volatilize, and finally by drug bearing microsphere suspension at 4 DEG C, 20000rpm centrifugation 10min obtained solid freeze-drying is removed
Water is placed on 4 DEG C of preservations.
The nano drug-carrying microsphere of gained PEG-PBL and adriamycin, average grain diameter 100nm, entrapment efficiency 85%.
Embodiment 2, the preparation for carrying taxol PEG-PBL nanosphere
150mg PEG-PBL (weight average molecular weight 10000, copolymerization ratios 1:1), 20mg taxol are weighed, 4mL dichloromethane is added
In alkane, 800rpm stirring 10min dissolves PEG-PBL and drug, then 30mL deionized water is added thereto, in 100MPa pressure
Under, colostric fluid is added into microjet homogenizer, 75 μm and 400 μm of runner processings, and homogeneous 3 times repeatedly are selected.100rpm
Stirring 12h makes solvent volatilize, and finally by drug bearing microsphere suspension at 4 DEG C, 20000rpm centrifugation 10min obtained solid freeze-drying is removed
Water is placed on 4 DEG C of preservations.The nano drug-carrying microsphere of gained PEG-PBL and taxol, average grain diameter 100nm, entrapment efficiency
It is 90%.
Embodiment 3, the preparation for carrying taxol PEG-PBL nanosphere
200mg PEG-PBL (weight average molecular weight 15000, copolymerization ratios 1:2), 20mg taxol are weighed, 4mL bis- is added
In chloromethanes, 1000rpm stirring 10min dissolves PEG-PBL and drug, then 30mL deionized water is added thereto, in 40MPa
Under pressure, colostric fluid is added into microjet homogenizer, selects 75 μm and 400 μm of runner processings, and homogeneous 3 times repeatedly.
100rpm stirring makes solvent volatilize for 24 hours, and finally by drug bearing microsphere suspension at 4 DEG C, 20000rpm is centrifuged the freezing of 15min obtained solid
Dry water removal is placed on 4 DEG C of preservations.
The nano drug-carrying microsphere of gained PEG-PBL and taxol, average grain diameter 150nm, entrapment efficiency 80%.
Embodiment 4, cell compatibility
By the L-929 cell of logarithmic growth phase DMEM culture medium (10% calf serum, 100 μ g/mL penicillin, 100 μ g/mL
Streptomysin) it is diluted to 1 × 104Cell/mL concentration, and add in each aperture of 96 orifice plates the cell solution of 100 μ L.It will
Cell inoculation contains 5%CO in 37 DEG C2CO2In incubator.After 24 hours, with 100 μ L 0.05,0.1,0.2,0.5 and 1mg/
ML polyethylene glycol gamma butyrolactone di-block copolymer solution or fresh culture replace former culture medium, contain 10% small ox blood
Clearly.200 μ L fresh cultures are used as negative control, and 200 μ L phenol solutions are used as positive control, after 24,48 and 72 hours, often
3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromide (MTT, 5mg/mL) of 30 μ L is added in a hole.Through 6 hours
All culture mediums are removed after incubation, and 150 μ L DMSO are added.Then plate is vibrated 10 minutes.Using microplate reader at 570nm
Measure OD value.All experiments are parallel to be carried out three times.It is calculated carefully with following equation by the ratio between test sample and the OD value of negative control
Born of the same parents' relative activity:
Relative activity (%)=(ODExperimental group/ODNegative control) × 100%
Use mtt assay evaluation drugloading rate for 10% carrier micelle vitro cytotoxicity.Choosing human lung carcinoma cell, (A549 is thin
Born of the same parents), culture is containing 10% calf serum, in the DMEM culture medium of 100 μ g/mL penicillin and 100 μ g/mL streptomysins.Pancreatin
Logarithmic phase cell is digested, is collected by centrifugation after termination, cell suspension is made, cell count adjusts its concentration to 1 × 105A/mL.Carefully
After born of the same parents' suspension prepares, cell is inoculated in 96 orifice plates with every 100 μ L of hole, 37 DEG C is subsequently placed in, contains 5%CO2Culture
In case.After cell is adherent for 24 hours, replacing with 100 μ L fresh cultures or contain drug concentration culture medium is 0.025 μ g/mL,
0.25 μ g/mL, 2.5 μ g/mL, 12.5 μ g/mL, 25 μ g/mL, the DMEM culture medium of the polypeptide drug-loaded micelle solution of 50 μ g/mL.Meanwhile
Have rated the cytotoxicity of the free drug of same concentrations.Use 100 μ L fresh cultured based sols as negative control, 100 μ L
Phenol solution is as positive control.After co-culturing 72h, culture medium is removed, the MTT solution of 20 μ L 5mg/mL is added.It is incubated for 5
After hour, all culture mediums are removed, 150 μ L dimethyl sulfoxides (DMSO) are added.Then, 96 orifice plates are placed on oscillator and are shaken
10min is swung, is measured at 570nm wavelength using microplate reader absorbance value (OD value).The relative growth rate (RGR) of cell is by surveying
The ratio calculation of the mean OD value of test agent and negative control obtains.
Claims (8)
1. a kind of preparation method of novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere, feature exist:
Polyethylene glycol gamma butyrolactone di-block copolymer, drug and volatile organic solvent are stirred into uniform oily phase
Solution A；
Deionized water is added into solution A, after microjet homogenizer is repeatedly homogeneous, obtains homogeneous latex emulsion B；
Lotion B stirs volatilization removing organic solvent at room temperature and acquires drug bearing microsphere suspension C；
By suspension C high speed refrigerated centrifuge, it is centrifuged obtained solid freeze-drying, that is, it is micro- to be prepared into the nano drug-carrying based on PEG-PBL
Ball.
2. preparation method according to claim 1, it is characterised in that:
In the step S1 shown in polyethylene glycol gamma butyrolactone di-block copolymer such as formula (I),
Wherein m is the degree of polymerization, 4≤m≤2000；N is the degree of polymerization, 2≤n≤1000.
3. preparation method according to claim 1, it is characterised in that: in the step S1 physically trapping hydrophobic drug be
Any active medicine of low solubility in aqueous solution or under hydrophilic environment, including it is not limited to anticancer drug (such as adriamycin, soft red
Mycin, methotrexate (MTX), mitomycin, camptothecin or Taxane family), analgesic or anti-inflammatory drug (such as Indomethacin), maincenter
Drugs for nervous, peripheral neverous system drug, circulatory system drug, medicine for respiratory system, medicine for digestive system, antiallergic
Object and hormone medicine；Organic solvent is methylene chloride, chloroform, tetrahydrofuran, acetonitrile, ether, any one in acetone；Oil
The concentration of copolymer is 1~50g/L in phase, and drug concentration is 0.1~10g/L；And mixing speed is 100~2000rpm, is stirred
Mixing the time is 10-30min.
4. preparation method according to claim 1, it is characterised in that: in the step S2 grease volume ratio be 0.1~
5；Chamber pressure in microjet homogenizer is 40MPa~200MPa；Cavity in microjet homogenizer is by following three kinds of sizes
Two compoundings in cavity obtain: 75 μm, 400 μm and 10mm；And the homogeneous number of microjet is 2-5 times.
5. preparation method according to claim 1, mixing speed described in the step S3 is 100~2000rpm, is stirred
Mix the time be 5~for 24 hours.
6. preparation method according to claim 1, the rate of the step S4 high speed refrigerated centrifuge is 15000~
25000rpm, time are 8~20min；And 10~1000nm of medicament-carrying nano-microsphere partial size.
7. in the evaluation of cell compatibility described according to claim 1, removing all culture mediums after 6 hours are incubated for, and be added
150μL DMSO.Then plate is vibrated 10 minutes.OD value is measured at 570nm using microplate reader.All experiments are parallel to carry out three
It is secondary.
8. in the experiment of anticancer activity described according to claim 1, all culture mediums are removed after 6 hours are incubated for, and be added 150
μL DMSO.Then 96 orifice plates are placed on oscillator and vibrate 10min, measure absorbance value at 570nm wavelength using microplate reader
(OD value).The relative growth rate (RGR) of cell is obtained by the ratio calculation of test sample and the mean OD value of negative control.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910863708.2A CN110478332A (en) | 2019-09-12 | 2019-09-12 | A kind of preparation method of novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910863708.2A CN110478332A (en) | 2019-09-12 | 2019-09-12 | A kind of preparation method of novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110478332A true CN110478332A (en) | 2019-11-22 |
Family
ID=68557854
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910863708.2A Pending CN110478332A (en) | 2019-09-12 | 2019-09-12 | A kind of preparation method of novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110478332A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112807485A (en) * | 2020-12-23 | 2021-05-18 | 青岛科技大学 | Injectable poly (4-hydroxybutyrate) (P4HB) porous microsphere preparation without stem cell and growth factor load |
| CN114426656A (en) * | 2022-01-28 | 2022-05-03 | 青岛科技大学 | Polymer nano hydrogel, drug delivery system comprising same and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101869712A (en) * | 2009-04-21 | 2010-10-27 | 财团法人工业技术研究院 | Medicinal composition used for treating tumor by utilizing polymeric micelles of cyst anticancer drugs |
| CN103479573A (en) * | 2013-07-26 | 2014-01-01 | 中国科学院长春应用化学研究所 | Preparation methods for polyethylene glycol monomethyl ether-polyester diblock copolymer micelle and drug-loaded micelle |
| CN107921005A (en) * | 2015-02-13 | 2018-04-17 | 友杏生技医药股份有限公司 | Utilize the composition and method of nano particle treatment tumour |
| CN108250415A (en) * | 2018-02-09 | 2018-07-06 | 青岛科技大学 | A kind of poly- (gamma-butyrolacton)-b- polylactic-acid block copolymers and preparation method thereof |
| CN109843971A (en) * | 2016-06-24 | 2019-06-04 | 阿科玛法国公司 | Nano-structured block copolymer film comprising biodegradable polyester block |
| CN110117359A (en) * | 2018-02-05 | 2019-08-13 | 青岛科技大学 | Poly- (gamma-butyrolacton) block copolymer of polyethers-b- and preparation method thereof |
-
2019
- 2019-09-12 CN CN201910863708.2A patent/CN110478332A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101869712A (en) * | 2009-04-21 | 2010-10-27 | 财团法人工业技术研究院 | Medicinal composition used for treating tumor by utilizing polymeric micelles of cyst anticancer drugs |
| CN103479573A (en) * | 2013-07-26 | 2014-01-01 | 中国科学院长春应用化学研究所 | Preparation methods for polyethylene glycol monomethyl ether-polyester diblock copolymer micelle and drug-loaded micelle |
| CN107921005A (en) * | 2015-02-13 | 2018-04-17 | 友杏生技医药股份有限公司 | Utilize the composition and method of nano particle treatment tumour |
| CN109843971A (en) * | 2016-06-24 | 2019-06-04 | 阿科玛法国公司 | Nano-structured block copolymer film comprising biodegradable polyester block |
| CN110117359A (en) * | 2018-02-05 | 2019-08-13 | 青岛科技大学 | Poly- (gamma-butyrolacton) block copolymer of polyethers-b- and preparation method thereof |
| CN108250415A (en) * | 2018-02-09 | 2018-07-06 | 青岛科技大学 | A kind of poly- (gamma-butyrolacton)-b- polylactic-acid block copolymers and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 李雪梅等: ""PHB及mPEG-PHB嵌段共聚物的合成与表征"", 《化学与生物工程》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112807485A (en) * | 2020-12-23 | 2021-05-18 | 青岛科技大学 | Injectable poly (4-hydroxybutyrate) (P4HB) porous microsphere preparation without stem cell and growth factor load |
| CN114426656A (en) * | 2022-01-28 | 2022-05-03 | 青岛科技大学 | Polymer nano hydrogel, drug delivery system comprising same and preparation method thereof |
| CN114426656B (en) * | 2022-01-28 | 2023-08-04 | 青岛科技大学 | Polymer nanohydrogels, drug delivery systems comprising the same, and methods of making the same |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10759905B2 (en) | Biodegradable amphiphilic polymer, polymeric vesicles prepared therefrom, and application of biodegradable amphiphilic polymer in preparation of medicines for targeted therapy of lung cancer | |
| Wang et al. | Preparation of tacrolimus loaded micelles based on poly (ɛ-caprolactone)–poly (ethylene glycol)–poly (ɛ-caprolactone) | |
| JP6677914B2 (en) | Specific targeted biodegradable amphiphilic polymers for ovarian cancer, polymer vesicles prepared therefrom and uses thereof | |
| CN105232459B (en) | A kind of poorly water soluble drugs polymer micelle composition and preparation method thereof redissolving self assembly | |
| CN108653236A (en) | A kind of biomembrane contains the preparation method and its usage of medicament nano crystal | |
| Zhao et al. | Paclitaxel-loaded poly (glycolide-co-ε-caprolactone)-b-D-α-tocopheryl polyethylene glycol 2000 succinate nanoparticles for lung cancer therapy | |
| CN105362251A (en) | DOTAP-mPEG-PLA nanoparticles, solution of nanoparticles, medicine-carrying compound as well as preparation method and application | |
| CN110478332A (en) | A kind of preparation method of novel polyethylene glycol gamma butyrolactone di-block copolymer nano drug-carrying microsphere | |
| CN103435718A (en) | PEG (polyethylene glycol)-modified hyaluronic acid cholesteryl ester | |
| CN106943378A (en) | Erythrocyte membrane encapsulating polyesters carry arsenic trioxide nanoparticle and preparation method thereof | |
| CN110403917A (en) | A kind of artificial excretion body, preparation method and application | |
| Wang et al. | pH-responsive nanomicelles of poly (ethylene glycol)-poly (ε-caprolactone)-poly (L-histidine) for targeted drug delivery | |
| CN101953776B (en) | Non-spherical drug-loaded particles and controlled release preparation of lactyl polymer and preparation methods thereof | |
| CN106750343B (en) | Y-shaped amphiphilic block copolymer, preparation method thereof and drug-loaded micelle taking copolymer as carrier for targeting intracellular drug release | |
| Yan et al. | A simple method for the synthesis of porous polymeric vesicles and their application as MR contrast agents | |
| Zhao et al. | Fabrication and characterization of dual drug-loaded poly (lactic-co-glycolic acid) fiber-microsphere composite scaffolds | |
| CN109316463B (en) | Composite nanoparticle and preparation method and application thereof | |
| CN110051652B (en) | PLGA/FK506 drug-loaded nano-microsphere as well as preparation method and application thereof | |
| CN110623924B (en) | Hydrophobic antibiotic-loaded polycaprolactone-polyethylene glycol nano micelle and preparation and application thereof | |
| CN104857502A (en) | Vascular endothelial growth factor loaded nano controlled-release compound and a preparation method thereof | |
| CN111450078A (en) | Electrostatic spinning nanoparticle-entrapped pharmaceutical preparation and application thereof | |
| CN105796529A (en) | Preparation method and applications of gambogic acid self-assembled polymer nanoparticles | |
| CN105902514A (en) | Nano-particles of ascorbyl palmitate | |
| CN105726511A (en) | Self-assembled polylysine graft nanoparticles and preparation and application thereof | |
| CN107383362A (en) | Hydrotropy polymer carrier and preparation method and application for insoluble drug delivering |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | 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: 20191122 |
|
| WD01 | Invention patent application deemed withdrawn after publication |