CN1857231A - Preparing process of biodegradable capsule loading medicine and nano magnetic particle - Google Patents
Preparing process of biodegradable capsule loading medicine and nano magnetic particle Download PDFInfo
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- CN1857231A CN1857231A CNA2006100341637A CN200610034163A CN1857231A CN 1857231 A CN1857231 A CN 1857231A CN A2006100341637 A CNA2006100341637 A CN A2006100341637A CN 200610034163 A CN200610034163 A CN 200610034163A CN 1857231 A CN1857231 A CN 1857231A
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- 239000003814 drug Substances 0.000 title claims abstract description 65
- 239000002775 capsule Substances 0.000 title claims abstract description 14
- 239000006249 magnetic particle Substances 0.000 title claims abstract description 9
- 238000011068 loading method Methods 0.000 title abstract description 5
- 238000000034 method Methods 0.000 title description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000004094 surface-active agent Substances 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 229920002988 biodegradable polymer Polymers 0.000 claims abstract description 6
- 239000004621 biodegradable polymer Substances 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims description 27
- 239000006185 dispersion Substances 0.000 claims description 23
- 239000002122 magnetic nanoparticle Substances 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- -1 poly-hydroxyl succinic acid, Chemical compound 0.000 claims description 14
- 239000002088 nanocapsule Substances 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 9
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000000839 emulsion Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 229930195573 Amycin Natural products 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
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- 235000010445 lecithin Nutrition 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 4
- 239000004626 polylactic acid Substances 0.000 claims description 4
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 3
- 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 claims description 3
- 229960000975 daunorubicin Drugs 0.000 claims description 3
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- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 claims description 2
- REKYPYSUBKSCAT-UHFFFAOYSA-N 3-hydroxypentanoic acid Chemical compound CCC(O)CC(O)=O REKYPYSUBKSCAT-UHFFFAOYSA-N 0.000 claims description 2
- DHHFDKNIEVKVKS-FMOSSLLZSA-N Betanin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC(C(=C1)O)=CC(C[C@H]2C([O-])=O)=C1[N+]2=C\C=C\1C=C(C(O)=O)N[C@H](C(O)=O)C/1 DHHFDKNIEVKVKS-FMOSSLLZSA-N 0.000 claims description 2
- DHHFDKNIEVKVKS-MVUYWVKGSA-N Betanin Natural products O=C(O)[C@@H]1NC(C(=O)O)=C/C(=C\C=[N+]/2\[C@@H](C(=O)[O-])Cc3c\2cc(O)c(O[C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O2)c3)/C1 DHHFDKNIEVKVKS-MVUYWVKGSA-N 0.000 claims description 2
- 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
- 108091093037 Peptide nucleic acid Proteins 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Chemical class 0.000 claims description 2
- 229920002730 Poly(butyl cyanoacrylate) Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 2
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 235000012677 beetroot red Nutrition 0.000 claims description 2
- 239000001654 beetroot red Substances 0.000 claims description 2
- 235000002185 betanin Nutrition 0.000 claims description 2
- 210000000349 chromosome Anatomy 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 2
- 239000008398 formation water Substances 0.000 claims description 2
- ROBFUDYVXSDBQM-UHFFFAOYSA-N hydroxymalonic acid Chemical compound OC(=O)C(O)C(O)=O ROBFUDYVXSDBQM-UHFFFAOYSA-N 0.000 claims description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 2
- 229960004857 mitomycin Drugs 0.000 claims description 2
- 230000004048 modification Effects 0.000 claims description 2
- 238000012986 modification Methods 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 229920001610 polycaprolactone Polymers 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000004848 polyfunctional curative Substances 0.000 claims description 2
- 108091033319 polynucleotide Proteins 0.000 claims description 2
- 102000040430 polynucleotide Human genes 0.000 claims description 2
- 239000002157 polynucleotide Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 229960003080 taurine Drugs 0.000 claims description 2
- 239000000052 vinegar Substances 0.000 claims description 2
- 235000021419 vinegar Nutrition 0.000 claims description 2
- 101150010487 are gene Proteins 0.000 claims 1
- 229960001967 tacrolimus Drugs 0.000 claims 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims 1
- 239000011248 coating agent Substances 0.000 abstract description 3
- 238000000576 coating method Methods 0.000 abstract description 3
- 239000002131 composite material Substances 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract 2
- 239000011258 core-shell material Substances 0.000 abstract 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 18
- 208000035126 Facies Diseases 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 10
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
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- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 8
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 8
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 6
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108010058846 Ovalbumin Proteins 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
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- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The preparation process of biodegradable capsule loading medicine and nanometer magnetic particle simultaneously includes: dissolving water soluble or hydrophilic medicine, modified nanometer magnetic particle and surfactant or emulsifier in water to obtain the dispersed system A; mixing biodegradable polymer and organic solvent to obtain dispersed system B; dispersing surfactant or emulsifier in water to obtain dispersed system C; mixing the dispersed system A, the dispersed system B and the dispersed system C to obtain composite emulsified system; and stirring the composite emulsified system fully to form the core-shell structure medicine-carrying nanometer magnetic capsule. The prepared medicine-carrying nanometer magnetic capsule has high coating rate, target and controllable medicine release and capacity of being monitored.
Description
Technical field
The present invention relates to biodegradable, the magnetic target administration in the medicine field and can implement the preparation method of the multiple-effect Nano capsule of the external real-time monitoring of medicine, more specifically refer to a kind of biodegradable nano magnetic capsule with medicine carrying of nuclear, shell structure, the stratum nucleare of drug loaded magnetic Nano capsule is made of jointly water solublity or hydrophilic medicament and magnetic nanoparticle, and shell is made up of biodegradated polymer materal.
Background technology
As everyone knows, the research of Nano medication is very vital new direction in the drug research, and drug main will be by sealing and method such as absorption is written in the nano-medicament carrier.Nanotechnology is used for drug research, has carried out work for many years abroad, and its particle size range broad how at 100~1000nm, is referred to as nanoparticle (nanosphere and nanocapsule), bigger microcapsule or the microsphere of then being called.Because the size ratio blood capillary diameter (6~8 μ m) of Nano medication is also little, thereby can enters with comparalive ease in the various histoorgans of human body and carry out sustained release, significantly improve bioavailability of medicament.The advantage that it also has many conventional medicines and is not had: slow releasing pharmaceutical changes the medicine half-life in vivo, the action time of prolong drug; Reach the purpose of targeting loading as " biological missile " after making targeted drug to certain organs; Guaranteeing to reduce survival dose under the prerequisite of drug effect, alleviating or eliminate toxic and side effects; Improve stability of drug, help storage; Change the film operative mechanism, increase medicine, help the performance of drug effect in drug transdermal absorption and the cell biomembranous permeability; Increase drug solubility.
At present, the application prospect of magnetic nano-particle in biological technical field is subjected to people's attention day by day.Magnetic nano particle can be used for clinical nuclear magnetic resonance, the disease various diseases that breaks; Magnetic nano particle also can be used as magnetic medium, combines with various carrier materials, is prepared into various magnetic steering nano-carrier, is used for disease treatment, and blood cell separates, purify DNA, and solid phase clone gene segment is analyzed various aspects such as bacteriotoxin.The magnetic drug-carrying nanoparticle that wherein is used for disease treatment is more as the research of anti-cancer medicament carrier, to treatment breast carcinoma, and the esophageal carcinoma, bladder cancer, skin carcinoma etc. have shown bigger advantage.The characteristics of this drug-supplying system are and can artificially control medicine-feeding part, make medicine accumulate and slowly discharge at target site, reach the effect that suppresses tumor growth and even eliminate tumor; On the other hand, reduce the dose of non-diseased region, thereby reduced the destruction of medicine normal human tissue.But the preparation of magnetic nano particle now mainly concentrates on magnetic nano liposome (referring to patent application: Paclitaxel liposome and preparation method thereof; CN200410052196.5); surface magnetic nanoparticle of coupling drug or magnetic nanoparticle coating medicine (referring to patent application: the method for making of nano-medicament carrier, CN02114356.0) wait medicine-carried system.These medicine-carried systems all have some limitations, and for example there is low envelop rate in the magnetic Nano lipid in application, and storage stability is low to discharge problems such as too fast with water soluble drug; Magnetic nanoparticle circulation time in human body of surface coupling drug, lip-deep water soluble drug, as polypeptide, protein etc. are destroyed by the various enzyme in the human body easily; The medicine-carried system of magnetic nanoparticle coating medicine needs to be heated to more than 100 ℃ in preparation process, is not suitable for the medicine that some are easy to thermal decomposition or thermal denaturation.In addition, when the nano magnetic iron oxide consumption acquires a certain degree, in human body, be difficult to be absorbed drainage, produce some side effect.The nano-sized iron oxide granule is very easy to be made medicine can not reach disease sites by other normal cytophagies in vivo simultaneously.
Nanometer Biodegradable high-molecular medicament capsule has very high dose and the good controlled capability taken, but targeting is relatively poor, is difficult in external real-time monitoring.
Summary of the invention
Purpose of the present invention will overcome above-mentioned shortcoming exactly, the preparation method of the biodegradable capsule of a kind of carrying medicament and nano magnetic particle is provided, prepared Nano capsule has the multiple-effect function, show as high drug loading, can implement targeting and controllable release, can adopt magnetic nuclear resonance method (MR), methods such as CT scan are in external characteristic such as monitor in real time.To treatment disease, research medicine distribute in vivo, developing new drug provides a kind of effective pharmaceutical carrier.
For reaching above-mentioned purpose, the capsular preparation method of the Biodegradable nanometer of carrying medicament of the present invention and magnetic-particle is as follows:
(1) with the surfactant of the magnetic nanoparticle of the water solublity of 800~5000 parts of quality or hydrophilic medicament, 0.1~80 part of mass parts quality and 2~30 parts of quality or emulsifiers dissolve in the water of 100 parts of quality, it is uniformly dispersed dispersed system A;
(2) organic solvent of the biodegradable polymer of 1~80 part of quality and 100 parts of quality is mixed after, it is uniformly dispersed, dispersion B;
(3) with the surfactant or the emulsifying agent of 0.1~50 part of quality and join in the water of 100 parts of quality, it is uniformly dispersed, dispersion C;
(4) with 1: 0.1~30 volume ratio the dispersions obtained A of being is joined among the dispersion B, formation water/oil type emulsion is uniformly dispersed, with 1: 1~10 volume ratio this emulsion is joined among the dispersions obtained C of being again, it is uniformly dispersed, water/oil/water type emulsion system;
(5) gained emulsion system is fully stirred, up to the organic solvent volatilization fully, organic solvent in the oil phase is diffused into water and volatilization, polymeric hardener in the oil phase forms nanoparticle, water solublity or hydrophilic medicament and magnetic nanoparticle are coated on the inside, form the drug loaded magnetic Nano capsule of core/shell structure.
Described Biodegradable high-molecular material can be a kind of, it also can be the mixture of two or more biodegradable polymer substances, not exclusively example includes but not limited to: polylactic acid, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly lactic coglycolic acid, polybutylcyanoacrylate, Polyalkylcyanoacrylanano, poly-epsilon-caprolactone and copolymer thereof, poly-anhydride, poly-beta-hydroxy valeric acid, poly-dioxane, poly-terephalic acid second vinegar, poly-hydroxyl succinic acid, poly-hydroxymalonic acid. and their copolymer.
The incomplete example of described hydrophilic or water soluble drug includes but not limited to: be gene, polypeptide, protein, polynucleotide, hereditary material, peptide nucleic acid(PNA), chromosome, tacrolimus (FK506), amycin, mitomycin, daunorubicin or paclitaxel, and other any water solublity or hydrophilic medicaments.
Described surfactant or emulsifying agent can be the mixture of a kind of material or several materials, and its incomplete example includes but not limited to: alkyl carboxylate, alkylsulfonate, alkyl sulfate salt, alkyl phosphate salt, quaternary ammonium salt, Fixanol, amine salt, polyoxyethylene compounds, polyvinyl alcohol, Polyethylene Glycol, sulfoxide compound, oxynitride, multicomponent alcoholics compound, oxireme-propylene oxide copolymer, amido propanoic acid, imidazoline, betanin, taurine, lecithin, fabaceous lecithin etc.
Described organic solvent is the mixture of a kind of solvent or several solvents, and its incomplete example includes but not limited to: dimethyl formamide, benzene, pyridine, Carbon bisulfide, dichloromethane, dioxane, methanol, chloroform, petroleum ether, carbon tetrachloride, oxolane, ethanol, ether, ethyl acetate, acetone, acetic acid etc.
As preferred version, described magnetic nanoparticle is a nanometer superparamagnetism ferroso-ferric oxide, and particle diameter is 5-50nm.For obtaining better effect, can carry out corresponding hydrophilic or hydrophobicity modification processing to nano oxidized iron surface according to the characteristic of medicine.
As optimum implementation, the mass ratio of the water among surfactant among the water among surfactant among described water solublity or hydrophilic medicament, magnetic nanoparticle, the dispersion A or emulsifying agent, the dispersion A, biodegradable polymer, organic solvent, the dispersion C or emulsifying agent and the dispersion C is: 150~300: 1~60: 0.5~2: 10: 5~50: 200: 5~35: 500.
In described (5) step, the preferred temperature when organic solvent diffusion and volatilization is 15~35 ℃, and preferred pressure is 1.01 * 10
5~6.70 * 10
-2Handkerchief.
The biodegradation type nano magnetic capsule of carrying medicament of the present invention, because the stratum nucleare of core/shell composite structure contains magnetic nanoparticle, capsule has the characteristics of magnetic target administration, has the multiple-effect function simultaneously, show as high drug loading, can implement targeting and controllable release, can adopt magnetic nuclear resonance method (MR), methods such as CT scan are in external characteristic such as monitor in real time.To treatment disease, research medicine distribute in vivo, developing new drug provides a kind of effective pharmaceutical carrier.Because the shell of the nano magnetic capsule of medicine carrying is the Biodegradable high molecular material, capsule has the characteristics of sustained-release administration in human body; When capsular particle diameter during, can pass through blood brain barrier less than 100nm.Thereby be particularly suited for treating the medicine of diseases such as tumor.
Preparation method technology of the present invention is simple, controlled, requires low to production equipment.The entrapment efficiency of prepared nano magnetic capsule can reach about 80%.
The specific embodiment
With embodiment the present invention is further specified again below.But embodiment does not limit content of the present invention.
Embodiment one
The aqueous solution of getting 3.5% (w/v) PVAC polyvinylalcohol of 3ml is interior water (being dispersion A), and 30mg ovalbumin and 0.8mg hydrophilic nano magnetic iron oxide particle are scattered in wherein, and the magnetic-particle particle diameter is the 5-50 nanometer; Organic facies (being dispersion B) is for being dissolved with the 6ml dichloromethane of 2.5% (w/v) PLGA; Outer water (being dispersion C) is the PVA 54ml aqueous solution of 0.4% (w/v) of stirring and dissolving.Join interior water in the organic facies and after (9500rpm) is uniformly dispersed it in homogenizer, joining outer aqueous phase again disperses, being stirred well to organic facies evaporates fully, PLGA separates out the curing balling-up, ovalbumin and magnetic ferroferric oxide are coated on the inside, form the drug loaded magnetic Nano capsule of core/shell structure.
Embodiment two
The aqueous solution of getting 4.5% (w/v) PVAC polyvinylalcohol of 3ml is interior water, and 45 milligrams of amycin and 1.2mg nano-magnetic ferroso-ferric oxide are scattered in wherein, and the magnetic-particle particle diameter is the 5-50 nanometer; Organic facies is for being dissolved with the 6ml dichloromethane of 6% (w/v) PLA; Outer water is the PVA 65ml aqueous solution of 0.5% (w/v) of stirring and dissolving.Join interior water in the organic facies and after (9500rpm) is uniformly dispersed it in dispersion machine, joining outer aqueous phase again disperses, fully stir the evaporative removal organic facies, PLA separates out the curing balling-up, amycin and magnetic ferroferric oxide are coated on the inside, form the drug loaded magnetic Nano capsule of core/shell structure.
Embodiment three
The sodium dodecyl sulfate aqueous solution of getting 6ml 5% (w/v) is interior water, and 30 milligrams of paclitaxels and 1.5mg nano-magnetic ferroso-ferric oxide are scattered in wherein; Organic facies is for being dissolved with the 6ml dichloromethane of 10% (w/v) PLGA; Outer water is the PVA 54ml aqueous solution of 0.4% (w/v) of stirring and dissolving.Join interior water in the organic facies and after (9500rpm) is uniformly dispersed it in blender, joining outer aqueous phase again disperses, fully stir the evaporative removal organic facies, PLGA separates out the curing balling-up, paclitaxel and ferroso-ferric oxide are coated on the inside, form the drug loaded magnetic Nano capsule of core/shell structure.
Embodiment four
The aqueous solution of getting 4.8% (w/v) PVAC polyvinylalcohol of 3ml is interior water, and 40 milligrams of daunorubicins and 1.8mg nano-magnetic ferroso-ferric oxide are scattered in wherein; Organic facies is for being dissolved with the 8ml ethyl acetate of 1% (w/v) PLGA and the mixture of acetone; Outer water is the sodium dodecyl sulfate aqueous solution 50ml of 3% (w/v) of stirring and dissolving.Join interior water in the organic facies and after (9500rpm) is uniformly dispersed it in blender, joining outer aqueous phase again disperses, fully stir the evaporative removal organic facies, PLGA separates out the curing balling-up, daunorubicin and superparamagnetism ferroso-ferric oxide are coated on the inside, form the drug loaded magnetic Nano capsule of core/shell structure.
Embodiment five
3% (w/v) lauryl sodium sulfate aqueous solution of getting 3ml is interior water, and 60 milligrams of amycin and 2.0mg nano-magnetic ferroso-ferric oxide are scattered in wherein; Organic facies is for being dissolved with the 6ml acetone of 1% (w/v) PLGA; Outer water is the PVA 80ml aqueous solution of 1% (w/v) of stirring and dissolving.Join interior water in the organic facies and after (9500rpm) is uniformly dispersed it in dispersion machine, joining outer aqueous phase again disperses, fully stir evaporation to remove organic facies, PLGA separates out the curing balling-up, amycin and superparamagnetism ferroso-ferric oxide are coated on the inside, form the drug loaded magnetic Nano capsule of core/shell structure.
Claims (7)
1, the preparation method of the biodegradable capsule of a kind of carrying medicament and nano magnetic particle is characterized in that may further comprise the steps:
(1) with the surfactant of the surface modification hydrophilic magnetic nano-particle of the water solublity of 800~5000 parts of quality or hydrophilic medicament, 0.1~80 part of quality and 1~50 part of quality or emulsifiers dissolve in the water of 100~5000 parts of quality, it is uniformly dispersed dispersed system A;
(2) organic solvent of the biodegradable polymer of 1~80 part of quality and 100 parts of quality is mixed after, it is uniformly dispersed, dispersion B;
(3) with the surfactant or the emulsifying agent of 0.1~50 part of quality and join in the water of 100 parts of quality, it is uniformly dispersed, dispersion C;
(4) with 1: 0.1~30 volume ratio the dispersions obtained A of being is joined among the dispersion B, formation water/oil type emulsion is uniformly dispersed, with 1: 1~10 volume ratio this emulsion is joined among the dispersions obtained C of being again, it is uniformly dispersed, water/oil/water type emulsion system;
(5) up to the organic solvent volatilization fully with the abundant stirring reaction of gained emulsion system, organic solvent in the oil phase is diffused into water and volatilization, polymeric hardener in the oil phase forms nanoparticle, water solublity or hydrophilic medicament and magnetic nanoparticle are coated on the inside, form the drug loaded magnetic Nano capsule of core/shell structure.
2, preparation method according to claim 1, it is characterized in that: described Biodegradable Polymers is polylactic acid, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly lactic coglycolic acid, polybutylcyanoacrylate, Polyalkylcyanoacrylanano, poly-epsilon-caprolactone and copolymer thereof, poly-anhydride, poly-beta-hydroxy valeric acid, a kind of or any one the above mixture in poly-dioxane, poly-terephalic acid second vinegar, poly-hydroxyl succinic acid, poly-hydroxymalonic acid. and their copolymer.
3, preparation method according to claim 1 is characterized in that: described hydrophilic or water soluble drug are gene, polypeptide, protein, polynucleotide, hereditary material, peptide nucleic acid(PNA), chromosome, tacrolimus, amycin, mitomycin, daunorubicin or paclitaxel.
4, preparation method according to claim 1 is characterized in that: described surfactant or emulsifying agent are one or more the mixture in alkyl carboxylate, alkylsulfonate, alkyl sulfate salt, alkyl phosphate salt, quaternary ammonium salt, Fixanol, amine salt, polyoxyethylene compounds, polyvinyl alcohol, Polyethylene Glycol, sulfoxide compound, oxynitride, multicomponent alcoholics compound, oxireme-propylene oxide copolymer, amido propanoic acid, imidazoline, betanin, taurine, lecithin, the fabaceous lecithin.
5, preparation method according to claim 1 is characterized in that: described organic solvent is one or more the mixture in dimethyl formamide, benzene, pyridine, Carbon bisulfide, dichloromethane, dioxane, methanol, chloroform, petroleum ether, carbon tetrachloride, oxolane, ethanol, ether, ethyl acetate, acetone, the acetic acid.
6, preparation method according to claim 1 is characterized in that: described magnetic nanoparticle is a super-paramagnetism nano ferriferrous oxide, and particle diameter is 5-50nm.
7, preparation method according to claim 1 is characterized in that: the mass ratio of the water among surfactant among the water among surfactant among described water solublity or hydrophilic medicament, magnetic nanoparticle, the dispersion A or emulsifying agent, the dispersion A, Biodegradable high-molecular, organic solvent, the dispersion C or emulsifying agent and the dispersion C is: 150~300: 1~60: 0.5~2: 10: 5~50: 200
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