CN108619525A - How smooth-mPEG-PLA nanoparticles of appropriate pyrrole and its preparation method and application - Google Patents
How smooth-mPEG-PLA nanoparticles of appropriate pyrrole and its preparation method and application Download PDFInfo
- Publication number
- CN108619525A CN108619525A CN201710439599.2A CN201710439599A CN108619525A CN 108619525 A CN108619525 A CN 108619525A CN 201710439599 A CN201710439599 A CN 201710439599A CN 108619525 A CN108619525 A CN 108619525A
- Authority
- CN
- China
- Prior art keywords
- smooth
- mpeg
- pla
- solution
- appropriate pyrrole
- 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.)
- Granted
Links
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims abstract description 218
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000000243 solution Substances 0.000 claims description 41
- 235000013339 cereals Nutrition 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000002512 chemotherapy Methods 0.000 claims description 9
- 239000007853 buffer solution Substances 0.000 claims description 8
- 206010047700 Vomiting Diseases 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000310 rehydration solution Substances 0.000 claims description 6
- 235000007164 Oryza sativa Nutrition 0.000 claims description 5
- 239000000644 isotonic solution Substances 0.000 claims description 5
- 235000009566 rice Nutrition 0.000 claims description 5
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 claims description 4
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000003340 retarding agent Substances 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 3
- 229950005499 carbon tetrachloride Drugs 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- LRWJZGCOPMDWFZ-UHFFFAOYSA-N phthalic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CC=C1C(O)=O LRWJZGCOPMDWFZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007974 sodium acetate buffer Substances 0.000 claims description 2
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 240000007594 Oryza sativa Species 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 239000008363 phosphate buffer Substances 0.000 claims 1
- 239000002504 physiological saline solution Substances 0.000 claims 1
- 239000001509 sodium citrate Substances 0.000 claims 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims 1
- 229960001790 sodium citrate Drugs 0.000 claims 1
- 235000011083 sodium citrates Nutrition 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 11
- 238000001338 self-assembly Methods 0.000 abstract description 7
- 229920000642 polymer Polymers 0.000 abstract description 3
- 238000004108 freeze drying Methods 0.000 abstract description 2
- 229920001427 mPEG Polymers 0.000 abstract 4
- 229920000747 poly(lactic acid) Polymers 0.000 description 70
- 239000004626 polylactic acid Substances 0.000 description 69
- 239000000126 substance Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000209094 Oryza Species 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- CPZBLNMUGSZIPR-NVXWUHKLSA-N palonosetron Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 CPZBLNMUGSZIPR-NVXWUHKLSA-N 0.000 description 4
- 229960002131 palonosetron Drugs 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000003186 pharmaceutical solution Substances 0.000 description 3
- -1 polyethylene Polymers 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 206010028813 Nausea Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229940029184 akynzeo Drugs 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000009514 concussion Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- WAXQNWCZJDTGBU-UHFFFAOYSA-N netupitant Chemical compound C=1N=C(N2CCN(C)CC2)C=C(C=2C(=CC=CC=2)C)C=1N(C)C(=O)C(C)(C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 WAXQNWCZJDTGBU-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- IGLKELDWPZFFKF-UHFFFAOYSA-N OC(C1=CC=CC=C1C(O)=O)=O.OC(C1=CC=CC=C1C(O)=O)=O.OC(C1=CC=CC=C1C(O)=O)=O.P.P Chemical compound OC(C1=CC=CC=C1C(O)=O)=O.OC(C1=CC=CC=C1C(O)=O)=O.OC(C1=CC=CC=C1C(O)=O)=O.P.P IGLKELDWPZFFKF-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229920000359 diblock copolymer Polymers 0.000 description 1
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960005163 netupitant Drugs 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- 229940065514 poly(lactide) Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 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 1
- 238000012360 testing method Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000003462 vein Anatomy 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/08—Solutions
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of medicaments, and in particular to how smooth mPEG PLA nanoparticles of appropriate pyrrole and its preparation method and application.Technical problem solved by the invention be to provide a kind of novel method solve the problems, such as how the smooth poorly water-soluble of appropriate pyrrole, wrap up how appropriate pyrrole is smooth using the amphipathic bis- block polymers of mPEG PLA, using the method for self assembly be prepared it is a kind of how the smooth mPEG PLA nanoparticles of appropriate pyrrole.The how appropriate smooth mPEG PLA nanoparticles of pyrrole have many advantages, such as that good water solubility, epigranular, freeze-drying can redissolve, easily absorb, can be injected intravenously.
Description
Technical field
The invention belongs to field of medicaments, and in particular to how smooth-mPEG-PLA nanoparticles of appropriate pyrrole and its preparation method and application.
Background technology
Currently, chemotherapy is the approach that malignant tumor patient continues life, due to the various adverse reactions in chemotherapy, serious shadow
Ring the quality of life of patient.From the perspective of biological evolution, vomiting belongs to a kind of mechanism of human body autoprotection, can be because of patient
Oneself state and be affected, can not control, can only mitigate completely.With the update of antiemetic, such as how appropriate pyrrole is smooth
(Netupitant) and the compound medicine of palonosetron (palonosetron) combine antiemetic, nearly the nausea of 98.5% patient,
Vomiting reaction substantially can complete incidence graph.
How appropriate pyrrole it is smooth be a kind of new drug, be mankind P- substances/neurokinine-1 (NK-1) receptor selective antagonists, and
NK-1 is nauseant Natural neurotransmitters in brain.As a kind of nk 1 receptor retarding agent, how appropriate pyrrole is smooth can be effectively pre-
The nausea and vomiting that anti-cancer chemotherapy acute stage and period of delay generate (in startup chemotherapy 25-120 hours), is currently under clinic
Experimental stage.The Akynzeo capsules that U.S. FDA approval on October 10th, 2014 Hesinn companies develop are that how appropriate pyrrole is smooth and pa
The compound medicine of palonosetron lists in the U.S., occurs nausea and vomiting when for preventing Chemotherapy in Patients.But how the smooth water of appropriate pyrrole
Dissolubility is poor, this defect limits its application in terms of pharmaceutical preparation, is especially difficult to form the pharmaceutical solutions such as ejection preparation.
Methoxy polyethylene glycol-polylactic acid (Methoxy poly (ethylene glycol)-poly (lactide), letter
Claiming mPEG-PLA) double block polymers are a kind of degradable, good biocompatibility amphipathic nature polyalcohols, in biomedical sector
There is important application.In the 1990s, having obtained batch of U.S. FDA containing the drug that PEG or PLA transport vehicles load
Standard is applied to clinic.MPEG-PLA copolymers contain hydrophilic block PEG and hydrophobic block PLA, can be self-assembled into aqueous solution
Nano particle has good application prospect in drug, Gene delivery system.Currently, the bis- block polymer nanometers of mPEG-PLA
The formulation for paclitaxel of grain carrier package has been applied to the clinical treatment of breast cancer in South Korea and Europe, and the II phases are also had been enter into the U.S.
Clinical test.
Invention content
Technical problem solved by the invention is to provide a kind of new method to wrap up how appropriate pyrrole is smooth, keeps its water solubility bright
It is aobvious to improve.The inventors discovered that modifying how appropriate pyrrole is smooth using amphipathic mPEG-PLA diblock copolymers, self assembly is utilized
Method can prepare a kind of novel water-soluble degradability nanoparticle, i.e., how smooth-mPEG-PLA the nanoparticles of appropriate pyrrole.How appropriate this is
Smooth-mPEG-PLA the nanoparticles of pyrrole have good water solubility, can form various pharmaceutical solutions, such as injection.
Amphipathic mPEG-PLA copolymers employed in the present invention, chemical name is methoxy polyethylene glycol-polylactic acid,
Abbreviation mPEG-PLA.Methoxy polyethylene glycol-polylactic acid nano particle has amphipathic, good biodegradability and biology
Compatibility increases drug circulation time in blood and bioavilability, sustained release and targeted delivery to increase
Drug effect reduces side effect.MPEG-PLA nanoparticles can be as the load of chemicals, genomic medicine, protein and vaccine etc.
Body.
Employed in the present invention how appropriate pyrrole is smooth, Chinese chemical name is known as 2- [3,5- bis- (trifluoromethyl) phenyl]-N, 2-
Dimethyl-N-[4- (2- aminomethyl phenyls) -6- (4- methylpiperazine-1-yls) pyridin-3-yl] propionamide；The entitled 2- of English language Chemical
[3,5-bis(trifluoromethy1)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-
methyIpiperazin-l-yl)pyridin-3-yI]propanamide；Molecular weight 578.60；Molecular formula C30H32F6N4O；
CAS registration numbers：290297-26-6 2 is the nausea generated novel prevention chemotherapy acute stage and period of delay and is vomitted
The drug spat.
First technical problem to be solved by this invention be to provide how the preparation of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole
Method takes raw material to be prepared according to following proportion relations：
Raw material：How appropriate pyrrole is smooth, mPEG-PLA copolymers；Wherein, how the smooth mass ratio with mPEG-PLA copolymers of appropriate pyrrole is
0.01~0.25；
Solvent：Dichloromethane, chloroform, acetone, tetrachloromethane, ethyl alcohol, methanol, ether, petroleum ether, pentane, ethyl acetate
Or at least one of hexamethylene；
Rehydration solution：At least one of water, isotonic solution or buffer solution；
Preparation method：By mPEG-PLA copolymers, how the smooth difference of appropriate pyrrole dissolving and mixing in a solvent, then will be molten
Agent is evaporated, be added appropriate rehydration solution slightly concussion it is complete to aquation, acquired solution be how the smooth-mPEG-PLA nanoparticles of appropriate pyrrole
Solution.
Preferably, above-mentioned how in the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, how appropriate pyrrole is smooth and mPEG-PLA
The mass ratio of copolymer is 0.25.
Preferably, above-mentioned how in the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, mPEG-PLA copolymers 80
Part, how smooth 20 parts of appropriate pyrrole.
Preferably, above-mentioned how in the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, the isotonic solution is made a living
Manage at least one of brine, 5% glucose solution or 0.149mol/L sodium bicarbonate solutions.
Preferably, above-mentioned how in the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, the buffer solution is phosphorus
Phthalate buffer, acetic acid-sodium acetate buffer solution, citric acid-sodium citrate buffer solution, disodium hydrogen phosphate-citrate buffer solution or
At least one of phthalic acid-hydrochloride buffer.
The present invention also provides it is above-mentioned how the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole be prepared it is how appropriate
Smooth-mPEG-PLA nanoparticles the solution of pyrrole.
The present invention also provides how smooth-mPEG-PLA the nanoparticles of appropriate pyrrole, the how appropriate pyrrole of transparency liquid is-mPEG-PLA nanometers smooth
Grain solution be drying to obtain how the smooth-mPEG-PLA nanoparticles of appropriate pyrrole.
Gained of the invention how the epigranular of the smooth-mPEG-PLA nanoparticles of appropriate pyrrole, average grain diameter is 58nm ± 10nm, average
Current potential is -0.57 ± 0.21mV, and character is stable in aqueous solution and freeze-drying can redissolve.
The present invention also provides it is above-mentioned how smooth-mPEG-PLA nanoparticles the solution of appropriate pyrrole or how smooth-the mPEG-PLA of appropriate pyrrole receives
Purposes of the grain of rice in preparing nk 1 receptor retarding agent.
The present invention also provides it is above-mentioned how smooth-mPEG-PLA nanoparticles the solution of appropriate pyrrole or how smooth-the mPEG-PLA of appropriate pyrrole receives
The grain of rice is preparing the purposes in preventing, treating or alleviating the drug of Nausea and vomiting caused by chemotherapy.
The method of the present invention uses the mode of self assembly, and with mPEG-PLA packages, how appropriate pyrrole is smooth, hence it is evident that improves how appropriate pyrrole is smooth
Water solubility, when the two ratio be 0.25 when, be prepared how the solubility of the smooth-mPEG-PLA nanoparticles of appropriate pyrrole in aqueous solution
About 20mg/mL, and the how appropriate smooth solubility in water of pyrrole of bulk pharmaceutical chemicals is only 0.00285mg/mL, with how appropriate pyrrole it is smooth effectively at
Divide to calculate, the smooth-mPEG-PLA nanoparticles water solubility of the how appropriate pyrrole of product of the present invention is at least 70 times of bulk pharmaceutical chemicals, and the present invention carries significantly
Risen how the smooth water solubility of appropriate pyrrole.Since how the smooth water solubility of appropriate pyrrole is very poor so the Akynzeo capsules just listed at present
For how appropriate pyrrole is smooth and the compound capsule of palonosetron, and mPEG-PLA packages is used to be self-assembly of the method for nanoparticle not
But effectively significantly improve how the smooth water solubility of appropriate pyrrole, and drug can be made to pharmaceutical solutions such as injection etc. and realized and is quiet
Arteries and veins is injected, and can make how appropriate pyrrole is smooth to be more easy to absorb in vivo by being injected intravenously to reach drug in the form of nanoparticle, and controllable
The release of pharmacy object, reaches slow releasing function in vivo.
Description of the drawings
The molecular structural formula of Fig. 1, (A) mPEG-PLA；(B) how the smooth molecular structural formula of appropriate pyrrole；
Fig. 2, how smooth-mPEG-PLA nanoparticles self assembly the schematic diagram of appropriate pyrrole；
Fig. 3, how the character phenogram of the smooth-mPEG-PLA nanoparticles of appropriate pyrrole：
(D) how the grain size distribution of the smooth-mPEG-PLA nanoparticles of appropriate pyrrole；
(E) how the potential image of the smooth-mPEG-PLA nanoparticles of appropriate pyrrole；
(F) how the scanning transmission electron microscope figure of the smooth-mPEG-PLA nanoparticles of appropriate pyrrole；
(G) how the appearance compares figure of the smooth-mPEG-PLA nanoparticles of appropriate pyrrole；Wherein control be it is single will how the smooth bulk pharmaceutical chemicals of appropriate pyrrole
The mixed solution (Wt=20mg/mL) of dispersion in aqueous solution.
Specific implementation mode
Due to how the smooth poorly water-soluble of appropriate pyrrole, in order to solve the problems, such as how the smooth poorly water-soluble of appropriate pyrrole, inventor done largely
Experimental study is intended to be carried out various modifications or modification, and it is smooth such as once to attempt to be made the how appropriate pyrrole of hydrochloride, water-soluble to improve
Property.
However be prepared how the smooth hydrochloride 1mg of appropriate pyrrole is dissolved in distilled water 1mL, as a result have been found that how the smooth hydrochloride of appropriate pyrrole
And it is undissolved, to judge make how the method for the smooth hydrochloride of appropriate pyrrole can not efficiently improve how appropriate pyrrole is smooth by how appropriate pyrrole is smooth
It is water-soluble.Then, inventor has carried out a variety of trials and has been carried out other modifications or modification again, all and failed.Finally pass through
A large number of experiments find, wrapped up in such a way that mPEG-PLA is using self assembly how appropriate pyrrole it is smooth be prepared how smooth-the mPEG- of appropriate pyrrole
PLA nanoparticles have it is water-soluble well, this method be effectively improved how the smooth water-soluble excellent process of appropriate pyrrole.
How the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, take raw material to be prepared according to following proportion relations：
Raw material：How appropriate pyrrole is smooth, mPEG-PLA copolymers；Wherein, how the smooth mass ratio with mPEG-PLA copolymers of appropriate pyrrole is
0.01~0.25；
Solvent：Dichloromethane, chloroform, acetone, tetrachloromethane, ethyl alcohol, methanol, ether, petroleum ether, pentane, ethyl acetate
Or at least one of hexamethylene；
Rehydration solution：At least one of water, isotonic solution or buffer solution；
Preparation method：By mPEG-PLA copolymers, how the smooth difference of appropriate pyrrole dissolving and mixing in a solvent, then will be molten
Agent is evaporated, be added appropriate rehydration solution slightly concussion it is complete to aquation, acquired solution be how the smooth-mPEG-PLA nanoparticles of appropriate pyrrole
Solution.
The present invention also provides it is above-mentioned how the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole be prepared it is how appropriate
Smooth-mPEG-PLA nanoparticles the solution of pyrrole.
The present invention also provides how smooth-mPEG-PLA the nanoparticles of appropriate pyrrole, the how appropriate pyrrole of transparency liquid is-mPEG-PLA nanometers smooth
Grain solution be drying to obtain how the smooth-mPEG-PLA nanoparticles of appropriate pyrrole.
The present invention also provides it is above-mentioned how smooth-mPEG-PLA nanoparticles the solution of appropriate pyrrole or how smooth-the mPEG-PLA of appropriate pyrrole receives
Purposes of the grain of rice in preparing nk 1 receptor retarding agent.
The present invention also provides it is above-mentioned how smooth-mPEG-PLA nanoparticles the solution of appropriate pyrrole or how smooth-the mPEG-PLA of appropriate pyrrole receives
The grain of rice is preparing the purposes in preventing, treating or alleviating the drug of Nausea and vomiting caused by chemotherapy.
If inventor's invention is when how the smooth mass ratio with mPEG-PLA copolymers of appropriate pyrrole is more than 0.25, nanoparticle self assembly
Effect is bad, drug can not be made to form nanoparticle completely.In the range of less than 0.25, can optionally it be adjusted according to concentration requirement
The two proportionate relationship.
Embodiment
Take how appropriate pyrrole smooth 20mg, mPEG-PLA 80mg are mixed in after being dissolved in respectively in 10mL dichloromethane in round-bottomed flask,
The pure water 1mL of 60 DEG C of addition after organic reagent is removed with Rotary Evaporators at 60 DEG C, it is slight to shake, until aquation is complete, shape
At how smooth-mPEG-PLA nanoparticles the solution of appropriate pyrrole.Obtained after the smooth-mPEG-PLA nanoparticles solution drying of the how appropriate pyrrole how appropriate pyrrole
Smooth-mPEG-PLA nanoparticles.
The characterization collection of illustrative plates of the drug-carrying nanometer particle is illustrated in fig. 3 shown below.Wherein Fig. 3 (D) is the grain size distribution of the nanoparticle.Its
In measure the average grain diameter of the nanoparticle and reach 58nm, Fig. 3 (E) is the potential image of the nanoparticle.Wherein measure the nanometer
The average potential of grain is -0.52mV, and Fig. 3 (F) is the transmission electron microscope picture of the nanoparticle.The nanoparticle known to transmission electron microscope detection
Grain size is small, and dispersion is uniform.Fig. 3 (G) is the figure that the appearance of the nanoparticle compares.Wherein control be it is single will how the smooth raw material of appropriate pyrrole
The mixed solution (Wt=20mg/mL) of medicine dispersion in aqueous solution.As seen from the figure, directly will how appropriate pyrrole tanga enters into water, medicine
Object is insoluble in water and tends to float to aqueous solution surface, has part to form crystallization in water.And by method of the present invention
The nanoparticle of preparation sees that solution is limpid transparent in appearance, completely without drug crystallization.
Claims (9)
1. how the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, it is characterised in that：Raw material is taken according to following proportion relations
It is prepared：
Raw material：How appropriate pyrrole is smooth, mPEG-PLA copolymers；Wherein, how the smooth mass ratio with mPEG-PLA copolymers of appropriate pyrrole is 0.01
~0.25；
Solvent：Dichloromethane, chloroform, acetone, tetrachloromethane, ethyl alcohol, methanol, ether, petroleum ether, pentane, ethyl acetate or ring
At least one of hexane；
Rehydration solution：At least one of water, isotonic solution or buffer solution；
Preparation method：By mPEG-PLA copolymers, how the smooth difference of appropriate pyrrole dissolves in a solvent, is then uniformly mixed, then by solvent
Be evaporated, be added appropriate rehydration solution until aquation completely to get how smooth-mPEG-PLA nanoparticles the solution of appropriate pyrrole.
2. it is according to claim 1 how the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, it is characterised in that：How
The smooth mass ratio with mPEG-PLA copolymers of appropriate pyrrole is 0.25.
3. it is according to claim 2 how the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, it is characterised in that：
80 parts of mPEG-PLA copolymers, how smooth 20 parts of appropriate pyrrole.
4. it is according to claim 1 how the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, it is characterised in that：Institute
The isotonic solution stated is at least one of physiological saline, 5% glucose solution or 0.149mol/L sodium bicarbonate solutions.
5. it is according to claim 1 how the preparation method of the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole, it is characterised in that：Institute
The buffer solution stated is phosphate buffer, acetic acid-sodium acetate buffer solution, citric acid-sodium citrate buffer solution, phosphoric acid hydrogen two
At least one of sodium-citrate buffer solution or phthalic acid-hydrochloride buffer.
6. being prepared by the preparation method of the smooth-mPEG-PLA nanoparticles solution of the how appropriate pyrrole of Claims 1 to 5 any one of them
How smooth-mPEG-PLA nanoparticles the solution of appropriate pyrrole.
7. how smooth-mPEG-PLA the nanoparticles of appropriate pyrrole, it is characterised in that：By described in claim 6 how smooth-the mPEG-PLA of appropriate pyrrole receives
Grain of rice solution drying gained.
8. described in claim 6 how described in the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole or claim 7 how appropriate pyrrole it is smooth-
Purposes of the mPEG-PLA nanoparticles in preparing nk 1 receptor retarding agent.
9. described in claim 6 how described in the smooth-mPEG-PLA nanoparticles solution of appropriate pyrrole or claim 7 how appropriate pyrrole it is smooth-
MPEG-PLA nanoparticles are preparing the purposes in preventing, treating or alleviating the drug of Nausea and vomiting caused by chemotherapy.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2017101527487 | 2017-03-15 | ||
| CN201710152748 | 2017-03-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108619525A true CN108619525A (en) | 2018-10-09 |
| CN108619525B CN108619525B (en) | 2020-12-29 |
Family
ID=63705644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710439599.2A Active CN108619525B (en) | 2017-03-15 | 2017-06-12 | Netupidem-mPEG-PLA nanoparticle and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108619525B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104053652A (en) * | 2011-11-29 | 2014-09-17 | 赫尔辛医疗股份公司 | Substituted 4-phenyl-pyridines for the treatment of NK-1 receptor related diseases |
| CN105878250A (en) * | 2014-10-29 | 2016-08-24 | 北京乐嘉宝医药科技有限责任公司 | Aprepitant nano composition |
-
2017
- 2017-06-12 CN CN201710439599.2A patent/CN108619525B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104053652A (en) * | 2011-11-29 | 2014-09-17 | 赫尔辛医疗股份公司 | Substituted 4-phenyl-pyridines for the treatment of NK-1 receptor related diseases |
| CN105878250A (en) * | 2014-10-29 | 2016-08-24 | 北京乐嘉宝医药科技有限责任公司 | Aprepitant nano composition |
Non-Patent Citations (1)
| Title |
|---|
| REN ZHONG XIAO等: "Recent advances in PeG–PLA block copolymer nanoparticles", 《INTERNATIONAL JOURNAL OF NANOMEDICINE》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108619525B (en) | 2020-12-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kang et al. | Enhancing the in vitro anticancer activity of albendazole incorporated into chitosan-coated PLGA nanoparticles | |
| CN104812381B (en) | Method for preparing therapeutic nano particle | |
| Wu et al. | Engineering bioresponsive hydrogels toward healthcare applications | |
| CN101940792B (en) | PCL-b-PEG-b-PCL carried hydrophobic medicine polymer vesica as well as preparation method and application thereof | |
| Tao et al. | Reduction-responsive gold-nanoparticle-conjugated Pluronic micelles: an effective anti-cancer drug delivery system | |
| KR100837860B1 (en) | Hydrophilic polymer nanocapsules and method for preparing the same | |
| Caldera et al. | Cyclic nigerosyl-1, 6-nigerose-based nanosponges: An innovative pH and time-controlled nanocarrier for improving cancer treatment | |
| CN104162169B (en) | A kind of preparation method of pharmaceutical composition | |
| CN105232459B (en) | A kind of poorly water soluble drugs polymer micelle composition and preparation method thereof redissolving self assembly | |
| CN101984958B (en) | Nanoscale albendazole micropowder and preparation method thereof | |
| Lal et al. | Design and development of a biocompatible montmorillonite PLGA nanocomposites to evaluate in vitro oral delivery of insulin | |
| CN102357077B (en) | Protein nanometer particle for wrapping slightly soluble medicines and preparation method thereof | |
| CN100546579C (en) | Temozolomide polylactic acid nano microsphere and preparation method thereof | |
| CA2495899A1 (en) | Solid nano pharmaceutical formulation and preparation method thereof | |
| CN103861112B (en) | Based on the pharmaceutical composition and preparation method thereof of polymer nano-particle carrier | |
| CN106983719A (en) | A kind of docetaxel polymer nano micelle injection, its preparation method and its application in tumor is prepared | |
| Kolawole et al. | Formulation and evaluation of paclitaxel-loaded boronated chitosan/alginate nanoparticles as a mucoadhesive system for localized cervical cancer drug delivery | |
| Stanisz et al. | Evaluation of cilazapril release profiles with the use of lignin-based spherical particles | |
| CN104434792A (en) | Polymer micelle, preparation method thereof, antitumor pharmaceutical composition, preparation and preparation method thereof | |
| CN109078184A (en) | Load double medicine nano particles and the preparation method and application thereof | |
| CN107137350A (en) | A kind of taxol polymer micelle and preparation method thereof | |
| CN109265658B (en) | Drug-loaded nanoparticle based on ferulic acid polymer and preparation method and application thereof | |
| CN106727429A (en) | A kind of targeting anti-tumor Nano medication for suppressing multidrug-resisting gene expression | |
| CN101011579B (en) | Application of cytoplasm-targeting chitosan oligosaccharide-aliphatic acid grafting medicinal-vector colloidal cluster | |
| Ibrahim et al. | Biosynthesized poly (3-hydroxybutyrate-co-3-hydroxyvalerate) as biocompatible microcapsules with extended release for busulfan and montelukast |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |