CN107496382A - Composite Nano capsule injection aquagel dual drug-loading slow-releasing system and preparation method - Google Patents
Composite Nano capsule injection aquagel dual drug-loading slow-releasing system and preparation method Download PDFInfo
- Publication number
- CN107496382A CN107496382A CN201710785162.4A CN201710785162A CN107496382A CN 107496382 A CN107496382 A CN 107496382A CN 201710785162 A CN201710785162 A CN 201710785162A CN 107496382 A CN107496382 A CN 107496382A
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- CN
- China
- Prior art keywords
- composite nano
- medicine
- water
- nano capsule
- injection aquagel
- Prior art date
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- Pending
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- 239000002131 composite material Substances 0.000 title claims abstract description 78
- 239000007924 injection Substances 0.000 title claims abstract description 74
- 238000002347 injection Methods 0.000 title claims abstract description 74
- 239000002088 nanocapsule Substances 0.000 title claims abstract description 66
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 230000009977 dual effect Effects 0.000 title claims abstract description 37
- 238000011068 loading method Methods 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims description 24
- 239000003814 drug Substances 0.000 claims abstract description 130
- 229920000642 polymer Polymers 0.000 claims abstract description 52
- 229940079593 drug Drugs 0.000 claims abstract description 51
- 239000000463 material Substances 0.000 claims abstract description 21
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 20
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- 230000037005 anaesthesia Effects 0.000 claims abstract description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 65
- 239000000243 solution Substances 0.000 claims description 35
- 239000007864 aqueous solution Substances 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 31
- 239000003995 emulsifying agent Substances 0.000 claims description 29
- 239000003960 organic solvent Substances 0.000 claims description 27
- 239000003921 oil Substances 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 239000000839 emulsion Substances 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 238000004945 emulsification Methods 0.000 claims description 19
- 238000002601 radiography Methods 0.000 claims description 19
- 239000012071 phase Substances 0.000 claims description 16
- 239000002775 capsule Substances 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 238000002604 ultrasonography Methods 0.000 claims description 13
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 12
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- 229920001661 Chitosan Polymers 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 229920005615 natural polymer Polymers 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 claims description 7
- 108010010803 Gelatin Proteins 0.000 claims description 7
- 239000008346 aqueous phase Substances 0.000 claims description 7
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- 235000011852 gelatine desserts Nutrition 0.000 claims description 7
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 6
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 6
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 6
- 229920002674 hyaluronan Polymers 0.000 claims description 6
- 229960003160 hyaluronic acid Drugs 0.000 claims description 6
- 229960004194 lidocaine Drugs 0.000 claims description 6
- 229920002521 macromolecule Polymers 0.000 claims description 6
- 238000000935 solvent evaporation Methods 0.000 claims description 6
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- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 210000000481 breast Anatomy 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Substances OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 5
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 5
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 claims description 4
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 claims description 4
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 claims description 4
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 4
- 108010025020 Nerve Growth Factor Proteins 0.000 claims description 4
- 102000015336 Nerve Growth Factor Human genes 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 4
- 239000013522 chelant Substances 0.000 claims description 4
- 229960003920 cocaine Drugs 0.000 claims description 4
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- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- 229960005015 local anesthetics Drugs 0.000 claims description 4
- 229910052748 manganese Inorganic materials 0.000 claims description 4
- 239000011572 manganese Substances 0.000 claims description 4
- 229960002409 mepivacaine Drugs 0.000 claims description 4
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 claims description 4
- 229940053128 nerve growth factor Drugs 0.000 claims description 4
- 229920002627 poly(phosphazenes) Polymers 0.000 claims description 4
- 150000004032 porphyrins Chemical class 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229960004919 procaine Drugs 0.000 claims description 4
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 claims description 4
- 229960001549 ropivacaine Drugs 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- -1 Cobalt amine Chemical class 0.000 claims description 3
- VTUSIVBDOCDNHS-UHFFFAOYSA-N Etidocaine Chemical compound CCCN(CC)C(CC)C(=O)NC1=C(C)C=CC=C1C VTUSIVBDOCDNHS-UHFFFAOYSA-N 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- 235000013339 cereals Nutrition 0.000 claims description 3
- 229960003976 etidocaine Drugs 0.000 claims description 3
- 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 claims description 3
- 229960005321 mecobalamin Drugs 0.000 claims description 3
- 239000011585 methylcobalamin Substances 0.000 claims description 3
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 claims description 3
- 235000007672 methylcobalamin Nutrition 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 3
- 229920000768 polyamine Polymers 0.000 claims description 3
- 229920000151 polyglycol Polymers 0.000 claims description 3
- 239000010695 polyglycol Substances 0.000 claims description 3
- 229960001807 prilocaine Drugs 0.000 claims description 3
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 102000008186 Collagen Human genes 0.000 claims description 2
- 108010035532 Collagen Proteins 0.000 claims description 2
- 240000007594 Oryza sativa Species 0.000 claims description 2
- 235000007164 Oryza sativa Nutrition 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 229920001436 collagen Polymers 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 239000008398 formation water Substances 0.000 claims description 2
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 claims description 2
- 239000003182 parenteral nutrition solution Substances 0.000 claims description 2
- 229920001451 polypropylene glycol Polymers 0.000 claims description 2
- 235000009566 rice Nutrition 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 229910017052 cobalt Inorganic materials 0.000 claims 1
- 239000010941 cobalt Substances 0.000 claims 1
- 229920000891 common polymer Polymers 0.000 claims 1
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- 238000013270 controlled release Methods 0.000 abstract description 6
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 229920006022 Poly(L-lactide-co-glycolide)-b-poly(ethylene glycol) Polymers 0.000 description 2
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 2
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- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
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- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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)
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K49/1803—Semi-solid preparations, e.g. ointments, gels, hydrogels
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- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1857—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
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Abstract
The invention discloses a kind of composite Nano capsule injection aquagel dual drug-loading slow-releasing system, include the nanocapsule and injection aquagel of entrapped drug；The average grain diameter of nanocapsule is 100nm~1000nm, and the w/v of composite Nano capsule and injection aquagel is 1:1~1:10；Injection aquagel includes high molecular polymer and crosslinking agent；Nanocapsule is prepared by polymer base material, local anesthetic, CO2 laser weld medicine or contrast agent can be encapsulated in nanocapsule, slow releasing function is played to medicine, injection aquagel matrix in dual drug-loading slow-releasing system can be positioned nanocapsule carrier in vivo, and whole drug controlled release system is fixed on into diseased region so as to be treated beneficial to the long-acting slow-release to diseased region.The present invention composite Nano capsule injection aquagel dual drug-loading slow-releasing system analgesia, oncotherapy, local anaesthesia, CO2 laser weld, etc. need the field of topical remedy's long-acting slow-release to have a good application prospect.
Description
Technical field
The present invention relates to biomedicine field, and in particular to a kind of composite Nano capsule-injection aquagel dual drug-loading delays
Release system and its preparation method and application.
Background technology
It is more and more to the demand of local anesthetic CO2 laser weld medicine with the development of medical technology, current part office
Portion's anaesthetic or CO2 laser weld medicine need low dose frequently to give because the biological half-life of medicine is shorter when clinically using
Medicine is brought larger painful and inconvenient with maintaining its drug effect to patient.Ultrasonic development is as a kind of nontoxic, safe and economical doctor
Image technology is learned, is widely used in medical science detection, but the part ultrasonic developer used at present also presence makes ultrasonic development
Image contrast it is relatively low the shortcomings that, therefore, study and improve biological half-life shorter local anesthetic or CO2 laser weld medicine
The fixation of thing and sustained release strengthen the slow releasing function of ultrasonic developer, improve the image of ultrasonic development to extend drug treating time
Contrast has being of great significance in clinical practice.
Microballoon is that drug molecule is wrapped in high molecular polymer by one kind, to realize that medicine is steadily released to mesh for a long time
Drug delivery system, the characteristics of delaying controlled release because of it gets the attention.Preparing the conventional method of microballoon mainly has emulsification
Solvent evaporation method, emulsion-crosslinking method, spray drying process, phase separation method etc..In emulsion-solvent evaporation method, because of drug carrier material
It is different from the hydrophily of packaging medicine property, the emulsion systems such as O/W, W/O, W/O/W or O/W/O type can be divided into.With carrier material
Exemplified by oil-soluble, carrier material is initially dissolved in a kind of organic solvent not miscible with water, then drug molecule it is scattered or
It is dissolved in carrier material solution, obtained solution or decentralized system, which need to add, carries out breast in the continuous phase aqueous phase containing emulsifying agent
Change to obtain discrete drop.In the curing process, organic solvent can be diffused in continuous phase first, and then in water/air circle
Face is volatilized, and during organic solvent volatilizees, microballoon is solidified, and finally obtains complete microballoon with drying process by collecting,
This is the single newborn emulsion-solvent evaporation methods of O/W (oil-in-water).For fat-soluble medicine, this method simple practical, but for water-soluble
Property medicine, then need using W/O/W (W/O/W) type solvent evaporation method for improveing on the basis of improveing on this basis：Medicine
It is initially dissolved in interior aqueous phase, then drug solution adds in oil phase and emulsifies by ultrasound or high-speed stirred and to form W/O colostrums, connects
Colostrum to add in outer aqueous phase, W/O/W emulsions are made, microballoon is finally obtained through centrifugation-cleaning-freeze-drying process.
Hydrogel is is swelled and keeps large quantity of moisture and undissolved polymer in water.Aquogel polymer has big
Amount absorbs the characteristic of moisture, and the moisture largely absorbed is full of in polymer network, be largely stretched in be crosslinked it is big
Strand, whole material is set to possess a kind of property of fluid, this and the full body tissue extremely phase for there are a large amount of waterborne liquids
Seemingly, soft, wetting surface and excitant is greatly reduced with the affine of tissue.Injection aquagel refers to there is a constant current
The hydrogel of method application that move property, that injection can be passed through.This compound has Thermo-sensitive, when embedding medicinal is injected into
After entering human body, it is transformed into biodegradable semi-solid gel under body temperature.
But existing research report, medicament slow-release microsphere focuses mostly on to be strengthened in micron level, the microballoon of packaging medicine
It need to be needed further to improve in terms of slow releasing function；Research for injection aquagel load medicine also concentrates on medicine and directly divided
Dissipate in aquogel system, yet there are no delaying for medicine for slow released nano microsphere-injection aquagel dual-sustained-release drug system
The research released, in particular for local anesthetic CO2 laser weld medicine, and in acoustic contrast agent.
Therefore, those skilled in the art, which is directed to developing a kind of composite Nano capsule-injection aquagel dual drug-loading, delays
System is released, increases the deenergized period of medicine, is solved above-mentioned in the prior art for local anesthetic CO2 laser weld medicine biology half
Phase of declining is shorter, and in acoustic contrast agent ultrasonic development image contrast it is relatively low the deficiencies of part.
The content of the invention
In view of the drawbacks described above of prior art, the purpose of the present invention is to solve the shortcomings of the prior art with medicine to sustained release
Demand, it is shorter to solve existing local anesthetic CO2 laser weld medicine biological half-life, and ultrasonic development in acoustic contrast agent
Image contrast it is relatively low the problems such as.A kind of composite Nano capsule-injection aquagel dual drug-loading slow-releasing system, preparation side are provided
Method and application.
To achieve the above object, the first aspect of the present invention provides a kind of composite Nano capsule-dual load of injection aquagel
Medicine slow-releasing system, is achieved through the following technical solutions：
A kind of composite Nano capsule-injection aquagel dual drug-loading slow-releasing system, including the nanocapsule of entrapped drug and can
Inject hydrogel；Wherein, the average grain diameter of the nanocapsule is 100nm~1000nm；
The injection aquagel includes the component of following weight percentage：4wt%~20wt% high molecular polymers,
0.1wt%~10wt% crosslinking agents；
The w/v of the composite Nano capsule and injection aquagel is 1:1~1:10.
Further, the high molecular polymer is natural polymerses or synthesising macromolecule copolymer；
Further, the natural polymerses are one kind in hyaluronic acid, collagen, gelatin, chitosan
Or several mixing；The synthesising macromolecule copolymer is PLA, PLA-PEG copolymer, poly lactic-co-glycolic acid
One or more of mixing in copolymer, poly-N-isopropyl acrylamide, carbomer；
Further, the crosslinking agent be BDO diepoxy ether, divinylsulfone, hydrazide compound, chitosan,
One or more in glutaraldehyde etc.；
Further, the nanocapsule is prepared by polymer base material；
Further, the polymer base material is oil-soluble polyphosphazene polymer lactic acid, poly lactic-co-glycolic acid, polyacrylic acid
Ester, PLA-PEG copolymer, PLA-polypropylene glycol copolymers, polylactic-co-glycolic acid-ethylene glycol copolymer
In one or more；
Further, the polymer base material molecular weight is 5000~100000；
Further, the medicine of the nanocapsule encapsulating is local anesthetic, CO2 laser weld class medicine, for ultrasound, CT
Or the medicine of MRI radiographies；
Second aspect of the present invention provides a kind of preparation side of composite Nano capsule-injection aquagel dual drug-loading slow-releasing system
Method, comprise the following steps：
Step 1, the composite Nano capsule that entrapped drug is prepared；
Step 2, crosslinking agent is added into the solution of high molecular polymer, stirring standing obtains injection aquagel；
Step 3, the injection aquagel for obtaining the composite Nano capsule and step 2 that are obtained in step 1 mix, and obtain compound
Nanocapsule-injection aquagel dual drug-loading slow-releasing system；
Wherein, composite Nano capsule and injection aquagel according to w/v are 1 in step 3:1~1:10 mixing.
Further, in the step 1, the preparation of composite Nano capsule comprises the following steps：
Step 1-1, the medicine for needing to encapsulate is dissolved with solvent respectively with polymer base material, ultrasound breast is carried out after mixing
Change, form water/fat liquor；
Step 1-2, the emulsion in step 1-1 is added in the aqueous solution containing emulsifying agent, carries out twice ultrasonic emulsification,
Obtain water/oil/water emulsion；
Step 1-3, the water obtained in step 1-2/oil/water emulsion is added in the aqueous solution containing emulsifying agent, stirred
Organic solvent is removed, obtains being encapsulated with the high molecular nanometer capsule aqueous solution of medicine；
Step 1-4, the high molecular nanometer capsule aqueous solution of the obtained entrapped drugs of step 1-3 is centrifuged, washing, ultrasound point
Dissipate, freeze-drying, obtain composite Nano capsule.
Further, in the step 1-1, polymer-based timber-used organic solvent dissolving；Medicine water or organic solvent are molten
Solution；
Wherein, the organic solvent is one kind in dichloromethane, chloroform, toluene, acetone, n-hexane or hexamethylene
It is or several；
Further, in the step 1-1, the concentration of polymer base material in organic solvent is 10mg/mL~100mg/
mL；The concentration of medicine in a solvent is 1mg/mL~30mg/mL；
Further, in the step 1-1, the aqueous phase of water/fat liquor and the volume ratio of oil phase are 1:1~1:10；
Further, in the step 1-1, step 1-2, the parameter of ultrasonic emulsification is 50W~300W, and emulsification times are
30s~200s；
Further, in the step 1-2, step 1-3, described emulsifying agent is polyvinyl alcohol, polyethylene glycol, carboxymethyl
One or more in glucan, chitosan；
Further, in the step 1-2, step 1-3, the weight hundred of emulsifying agent in the aqueous solution containing emulsifying agent
It is 0.01wt%~10wt% to divide content；Concentration of the emulsifying agent in emulsion system is 0.1mg/mL~50mg/mL；
Further, in the step 1-4, centrifugation rate is 8000rpm~15000rpm；The freeze-drying temperature
For -30 DEG C.
Further, in the step 2, crosslinking agent is BDO diepoxy ether, divinylsulfone, hydrazides chemical combination
One or more in thing, chitosan etc.；
Further, in the step 2, the weight percentage of high molecular polymer is in macromolecule polymer solution
4wt%~20wt%；Weight percentage of the crosslinking agent in the solution of high molecular polymer be 0.1wt%~
10wt%；
Further, in the step 2, stirring dwell temperature is 20 DEG C~50 DEG C；Time is 4~20 hours；
Entrapped drug described above medicine as described in first aspect present invention defines.
Third aspect present invention additionally provides above-mentioned composite Nano capsule-injection aquagel dual drug-loading slow-releasing system and made
Standby local anesthetic preparation, CO2 laser weld class pharmaceutical preparation, the application for ultrasonic, CT or MRI radiographies pharmaceutical preparation.
It is used for office in preparation present invention also offers above-mentioned composite Nano capsule-injection aquagel dual drug-loading slow-releasing system
Purposes in portion's anesthesia, CO2 laser weld, radiography related drugs.
The present invention also provides a kind of Drug controlled release, the method for improving medicine stability, and it is included medicine in need
Thing is applied after being prepared as above-mentioned composite Nano capsule-injection aquagel dual drug-loading slow-releasing system to the person of needs；
Medicine described above is selected from local anesthetic, CO2 laser weld class medicine, radiography medicine；
The local anesthetic include but is not limited to lidocaine, Bupivacaine, mepivacaine, Bupivacaine, according to for card
Cause, prilocaine, ropivacaine etc., procaine (slave's fluorine cacaine), chloroprocanine, totokaine, cocaine etc.；
The CO2 laser weld class medicine includes but is not limited to Basic Fibroblast Growth Factor, nerve growth factor, cranial nerve
Auxin parenteral solution, Mecobalamin injection, Pu Lining potassium etc.；
The radiography medicine includes but is not limited to for fluorocarbon liquid, Iodic agent, Gd-DTPA and its line style, ring-like polyamines
The porphyrin chelate etc. of more carboxylic class chelates, manganese.
In composite Nano capsule-injection aquagel dual drug-loading slow-releasing system of the present invention, nanocapsule entrapped drug disperses
In injection aquagel, play a part of slowly discharging；Injection aquagel good biocompatibility, nanocapsule carrier can be existed
Effect is fixed on the positioning in vivo, whole drug controlled release system is fixed on diseased region so as to beneficial to the long-acting of diseased region
Slow release treatment, to comprising medicament-carried nano capsule can play a part of medicine and fix and dual-sustained-release.
Composite Nano capsule-injection aquagel dual drug-loading slow-releasing system of the present invention is applied to local anesthetic
When, dual slow releasing function adds the constant drug effect time of medicine, reduces the administration number of times of medicine, reduces the pain of patient
Bitter and inconvenience.
Composite Nano capsule-injection aquagel dual drug-loading slow-releasing system of the present invention is applied to CO2 laser weld class medicine
When, injection aquagel is transformed into biodegradable semi-solid after medicine-feeding part human body is injected under body temperature
Gel, fixed and slow releasing function is played to CO2 laser weld medicine, drug treating time is extended, improves curative effect.
Composite Nano capsule-injection aquagel dual drug-loading slow-releasing system of the present invention is made applied to ultrasound, CT or MRI
During shadow medicine, its medicine is fixed and dual-sustained-release characteristic improves radiography image contrast, improves the accuracy of Angiographic,
Substantially reduce the probability of the erroneous judgement for the disease thus brought.
In summary, composite Nano of the invention capsule-injection aquagel dual drug-loading slow-releasing system and prior art phase
Than, have can improve medicine stability, Drug controlled release, medicine local positioning fix and drug targeting site transport etc. it is excellent
Point, it can reach and reduce drug administration number, improve patient's compliance and reduce poisonous side effect of medicine, improve radiography image contrast
Degree, improves the accuracy of Angiographic, substantially reduces the erroneous judgement probability of disease, beneficial effect is obvious in clinical practice, has
Highly important meaning and application value.
Brief description of the drawings
Fig. 1 is the morphosis and particle size dispersion figure that the composite Nano capsule of embodiment 1 is observed through transmission electron microscope.
Embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercially available prod.
The invention provides a kind of composite Nano capsule-injection aquagel dual drug-loading slow-releasing system, including entrapped drug
Nanocapsule and injection aquagel；Wherein, the average grain diameter of the nanocapsule is 100nm~1000nm；The injectable water
Gel includes the component of following weight percentage：2wt%~10wt% natural polymerses, 0.1wt%~5wt% are handed over
Join agent；The natural polymerses are hyaluronic acid, gelatin；The crosslinking agent is BDO diepoxy ether, penta 2
Aldehyde；The w/v of the composite Nano capsule and injection aquagel is 1:3~1:5.
In preferrred embodiment of the present invention, the nanocapsule is by polymer base material via emulsion process-solvent evaporation method
It is prepared；
Wherein, the polymer base material is oil-soluble polyphosphazene polymer lactic acid, poly lactic-co-glycolic acid, PLA-poly- second two
Alcohol copolymer, polylactic-co-glycolic acid-ethylene glycol copolymer；The polymer base material molecular weight is 5000~100000, excellent
Select 20000；
In preferrred embodiment of the present invention, the medicine of the nanocapsule encapsulating is local anesthetic, CO2 laser weld class
Medicine, for ultrasound, CT or MRI radiographies medicine；
In preferrred embodiment of the present invention, the local anesthetic is local anesthetics of amide derivatives, such as lidocaine,
Bupivacaine, mepivacaine, Bupivacaine, Etidocaine, prilocaine, ropivacaine etc.；
Portion's anaesthetic is esters local anaesthetics, for example, procaine (slave's fluorine cacaine), chloroprocanine, totokaine,
Cocaine etc.；
The CO2 laser weld class medicine is Basic Fibroblast Growth Factor, nerve growth factor, cranial nerve growthine injection
Liquid, Mecobalamin injection, Pu Lining potassium etc.；
The medicine for ultrasound, CT or MRI radiographies is fluorocarbon liquid, Iodic agent, Gd-DTPA and its line style, ring
Porphyrin chelate of the more carboxylic class chelates of type polyamines and manganese etc..
The invention provides a kind of preparation method of composite Nano capsule-injection aquagel dual drug-loading slow-releasing system, bag
Include following steps：
Step 1, the composite Nano capsule that entrapped drug is prepared；
Step 2, added in equal volume into the high molecular polymer aqueous solution that weight percentage is 4wt%~20wt%
Weight percentage is 0.2wt%~10wt% cross-linking agent aqueous solution, and 4~20 are stood after being stirred at 20 DEG C~50 DEG C
Hour obtains injection aquagel；
Step 3, the injection aquagel for obtaining the composite Nano capsule and step 2 that are obtained in step 1 are according to bulking value
Than for 1:3~1:5 mixing, obtain composite Nano capsule-injection aquagel dual drug-loading slow-releasing system；
Wherein, in the step 2, crosslinking agent is BDO diepoxy ether, glutaraldehyde.
In preferrred embodiment of the present invention,
When the medicine encapsulated in composite Nano capsule is water soluble drug, in the step 1, the preparation side of composite Nano capsule
Method comprises the following steps：
Step 1-1a, the water soluble drug for needing to encapsulate is dissolved with water, polymer-based timber-used organic solvent dissolved, medicine
Thing it is water-soluble it is solidifying mixed with polymer base material organic solution after carry out ultrasonic emulsification, formation water/fat liquor；
Step 1-2a, water/fat liquor in step 1-1a is added in the aqueous solution containing emulsifying agent, carried out secondary super
Sound emulsifies, and obtains water/oil/water emulsion；
Step 1-3a, the water obtained in step 1-2a/oil/water emulsion is added in the aqueous solution containing emulsifying agent, stirred
Removing organic solvent is mixed, obtains being encapsulated with the high molecular nanometer capsule aqueous solution of medicine；
Step 1-4a, the high molecular nanometer capsule aqueous solution of the obtained entrapped drugs of step 1-3a is centrifuged, washing, ultrasound point
Dissipate, be freeze-dried after repeating this centrifugation-cleaning-dispersion process 3~10 times, obtain composite Nano capsule.
In preferrred embodiment of the present invention,
When the medicine encapsulated in composite Nano capsule is ester soluble drug, in the step 1, the preparation side of composite Nano capsule
Method comprises the following steps：
Step 1-1b, the medicine for needing to encapsulate is dissolved with polymer-based timber-used organic solvent, collectively as oil phase and water
Mixing carries out ultrasonic emulsification, forms water/fat liquor；
Step 1-2b, water/fat liquor in step 1-1b is added in the aqueous solution containing emulsifying agent, carried out secondary super
Sound emulsifies, and obtains water/oil/water emulsion；
Step 1-3b, the water obtained in step 1-2b/oil/water emulsion is added in the aqueous solution containing emulsifying agent, stirred
Removing organic solvent is mixed, obtains being encapsulated with the high molecular nanometer capsule aqueous solution of medicine；
Step 1-4b, the high molecular nanometer capsule aqueous solution of the obtained entrapped drugs of step 1-3b is centrifuged, washing, ultrasound point
Dissipate, be freeze-dried after repeating this centrifugation-cleaning-dispersion process 3~10 times, obtain composite Nano capsule.
In preferrred embodiment of the present invention, in the step 1-1a, step 1-1b, organic solvent be dichloromethane,
One or more in chloroform, toluene, acetone, n-hexane or hexamethylene；
In preferrred embodiment of the present invention, in the step 1-1a, step 1-1b, polymer base material is in organic solvent
In concentration be 10~100mg/mL, preferably 25~100mg/mL；
Concentration of the medicine in water or organic solvent is 1~30mg/mL, preferably 5~20mg/mL；
In preferrred embodiment of the present invention, in the step 1-1a, step 1-1b, aqueous phase and the oil of water/fat liquor
The volume ratio of phase is 1:1~1:10, preferably 1:5；
In preferrred embodiment of the present invention, in the step 1-1a, step 1-1b, step 1-2a, step 1-2b, surpass
The parameter of sound emulsification is 50~300W, preferably 60~90W；
Emulsification times are 30~200s, preferably 30s；
In preferrred embodiment of the present invention, the step 1-2a, step 1-2b, step 1-3a, step 1-3b, in,
Described emulsifying agent is the one or more in polyvinyl alcohol, polyethylene glycol, Sensor Chip CM 5, chitosan；
In preferrred embodiment of the present invention, the step 1-2a, step 1-2b, step 1-3a, step 1-3b, in,
The weight percentage of emulsifying agent is 0.01wt%~10wt% in the aqueous solution containing emulsifying agent, preferably 0.1wt%~
4wt%；
Concentration of the emulsifying agent in emulsion system is 0.1~50mg/mL；
In preferrred embodiment of the present invention, in the step 1-4a, step 1-4b, centrifugation rate be 8000~
15000rpm；The freeze-drying temperature is -30 DEG C.
Medicine medicine definition as described above described in preparation method of the present invention in entrapped drug.
Technical scheme is elaborated with reference to embodiment：The present embodiment is with technical solution of the present invention
Premised under implemented, give detailed embodiment and specific operating process, but protection scope of the present invention is unlimited
In following embodiments.
The preparation of embodiment 1, composite Nano capsule
By 1ml lidocaine hydrochloride injections and the dichloromethane of 5ml polylactic acid-polyglycols polymer (PLA-MPEG)
Solution mixes, and wherein the molecular weight of PLA-MPEG polymer is 20000, m (MPEG):M (PLA)=1:3, lidocaine hydrochloride note
The concentration for penetrating liquid is 20mg/ml, the concentration 25mg/ml of polylactic acid-polyglycol, and 30s is emulsified using 150W power ultrasonic, then
The polyvinyl alcohol water solution 10ml of mass fraction 4% is added, using 90W second of ultrasonic emulsification 30s of power.Add quality
The polyvinyl alcohol water solution 20ml of fraction 0.1% magnetic agitation 6h at room temperature, after dichloromethane volatilization completely, with
12000rpm speed centrifuges 20min to gained water/oil/water emulsion, rehydration of laying equal stress on washes-ultrasonic disperse-centrifugal process three times, freeze
Composite Nano capsule is collected after dry.
By pattern and particle size dispersion feelings of the composite Nano capsule through transmission electron microscope observing of the encapsulating lidocaine being prepared
Condition, display, composite Nano capsule profile prepared by embodiment 1 is mellow and full, smooth, and particle size dispersion is between 70nm~800nm, such as accompanying drawing
Shown in 1.
The preparation of embodiment 2, composite Nano capsule
By 1ml procaine hydrochloride injections and 5ml PLGAs-polyethylene glycol polymer (PLGA-
PEG dichloromethane solution mixing), the wherein molecular weight of PLGA-MPEG polymer are 20000, LA:GA=50:50, m
(MPEG):M (PLA)=1:3, the concentration of procaine hydrochloride injection is 5mg/ml, PLGA-PEG concentration 50mg/ml, is adopted
30s is emulsified with 150W power ultrasonic, adds the polyvinyl alcohol water solution 20ml of mass fraction 1%, using 90W power the
Twice ultrasonic emulsifies 30s.The polyvinyl alcohol water solution 20ml of mass fraction 0.1% magnetic agitation 6h at room temperature is added, is treated
After dichloromethane volatilization completely, 20min is centrifuged to gained water/oil/water emulsion with 12000rpm speed, rehydration of laying equal stress on is washed-surpassed
Sound is scattered-centrifugal process three times, collect composite Nano capsule after freezing.
The preparation of embodiment 3, composite Nano capsule
Radiography Iodic agent iodized oil and PLA are dissolved in acetone and form oil phase, the wherein concentration 5mg/ of iodized oil
Ml, the concentration 100mg/ml of PLA.Take oil-phase solution 5ml to be mixed with 1ml ultra-pure waters, emulsified using 150W power ultrasonic
30s, the polyvinyl alcohol water solution 20ml of mass fraction 1% is added, after 90W power ultrasonic emulsification 30s, add matter
The polyvinyl alcohol water solution 20ml magnetic agitation 4h at room temperature of fraction 0.1% are measured, after acetone volatilization completely, with 8000rpm
Speed 20min is centrifuged to gained fat liquor, rehydration of laying equal stress on washes-ultrasonic disperse-centrifugal process three times, collect compound receive after lyophilized
Rice capsule.
The preparation of embodiment 4, composite Nano capsule
Perflexane and PLA are dissolved in acetone and form oil phase, the wherein concentration 20mg/ml of perflexane, PLA
Concentration 50mg/ml.Take oil-phase solution 5ml to be mixed with 1ml ultra-pure waters, 30s is emulsified using 90W power ultrasonic, adds matter
The polyvinyl alcohol water solution 20ml mixing of fraction 4% is measured, after 60W power ultrasonic emulsification 30s, adds mass fraction
0.1% polyvinyl alcohol water solution 20ml magnetic agitation 4h at room temperature, after acetone volatilization completely, with 12000rpm speed
20min is centrifuged to gained emulsion, rehydration of laying equal stress on washes-ultrasonic disperse-centrifugal process three times, collect composite Nano capsule after freezing.
The preparation of embodiment 5, composite Nano capsule-injection aquagel dual drug-loading slow-releasing system
Using the NaOH solution of 0.3mol/L concentration as medium, the hyaluronic acid solution of mass fraction 20%, stirring are prepared
Uniformly.Crosslinking agent 1,4- butanediol diepoxy ethers are configured to the molten of mass fraction 2% using same concentration NaOH solution as medium
Liquid, take and mixed in equal volume with hyaluronic acid solution, reaction system is placed in 25 DEG C of water-baths after stirring 1h and reacts 6h, is obtained sticky
Gel.Lidocaine-polylactic acid poly ethylene glycol composite Nano capsule the 10mg and 30ml hyalomitomes collected after being freezed in embodiment 1
Acid gel is mixed, and composite Nano capsule-injection aquagel dual drug-loading sustained release of lidocaine must be encapsulated after 25 DEG C of stirring 2h
System.
The drug release in vitro situation of the detection observation composite Nano capsule-injection aquagel dual drug-loading slow-releasing system,
The display present invention implements composite Nano capsule-injection aquagel dual drug-loading sustained release of the 5 encapsulating lidocaines being prepared
Good result of the system with slowly release, stable medicine.
The preparation of embodiment 6, composite Nano capsule-injection aquagel dual drug-loading slow-releasing system
The aqueous gelatin solution that mass fraction is 10% is prepared, mass fraction is prepared using glutaraldehyde as crosslinking agent as 0.5%
Glutaraldehyde water solution.Isometric aqueous gelatin solution is mixed with glutaraldehyde water solution, is placed in reaction system after stirring 1h
3h is reacted in 40 DEG C of water-baths, obtains viscous gel.Perflexane-PLA the composite Nano collected after being freezed in embodiment 4
Capsule 10mg is mixed with 30ml gelatin gels, and composite Nano capsule-injection aquagel of perflexane must be encapsulated after 40 DEG C of stirring 2h
Dual drug-loading slow-releasing system.
The medicament dual carried medicine sustained-release system of composite Nano capsule-injection aquagel of the encapsulating perflexane is observed in body
Outer release conditions, composite Nano capsule-injection aquagel dual drug-loading sustained release of encapsulating perflexane prepared by display embodiment 6
System can carry out more than 10 hours long lasting for radiography, it is ultrasound, CT or MRI radiographies to be advantageous to improve using fluorocarbon liquid
The radiography image contrast that medicine is detected, improve the accuracy of Angiographic.
In summary, composite Nano capsule-injection aquagel dual drug-loading slow-releasing system of technical solution of the present invention and its
Preparation method, can improve medicine stability, Drug controlled release, medicine local positioning fix and drug targeting site transport etc. it is excellent
Point, drug administration number is advantageously reduced, improve patient's compliance and reduces poisonous side effect of medicine, improves radiography image contrast
Degree, improves the accuracy of Angiographic, substantially reduces the erroneous judgement probability of disease, being advantageous to improve in existing clinical practice has deficiency
Part, tool is of great significance and application value.
Specific embodiment of the invention described in detail above.It should be appreciated that the ordinary skill of this area is without creative
Work can makes many modifications and variations according to the design of the present invention.Therefore, all structures under this invention in the art
Think the technical scheme obtained on the basis of existing technology by logical analysis, reasoning, or a limited experiment, all should be in right
Determined by claim in protection domain.
Claims (10)
- A kind of 1. composite Nano capsule-injection aquagel dual drug-loading slow-releasing system, it is characterised in that receiving including entrapped drug Rice capsule and injection aquagel；Wherein, the average grain diameter of the nanocapsule is 100nm~1000nm；The injection aquagel includes the component of following weight percentage：4wt%~20wt% high molecular polymers, 0.1wt%~10wt% crosslinking agents；The w/v of the composite Nano capsule and injection aquagel is 1:1~1:10.
- 2. slow-releasing system according to claim 1, it is characterised in that the high molecular polymer is natural polymerses Or synthesising macromolecule copolymer；Wherein, the natural polymerses are that the one or more in hyaluronic acid, collagen, gelatin, chitosan are mixed Close；The synthesising macromolecule copolymer be PLA, PLA-PEG copolymer, Poly(D,L-lactide-co-glycolide, One or more of mixing in poly-N-isopropyl acrylamide, carbomer；The crosslinking agent is in 1,4- butanediol diepoxies ether, divinylsulfone, hydrazide compound, chitosan, glutaraldehyde etc. It is one or more of.
- 3. slow-releasing system according to claim 1, it is characterised in that the nanocapsule is prepared by polymer base material；Wherein, the polymer base material is oil-soluble polyphosphazene polymer lactic acid, poly lactic-co-glycolic acid, polyacrylate, poly- breast One kind in acid-ethylene glycol copolymer, PLA-polypropylene glycol copolymers, polylactic-co-glycolic acid-ethylene glycol copolymer It is or a variety of.The medicine of the nanocapsule encapsulating is local anesthetic, CO2 laser weld class medicine, for ultrasound, the medicine of CT or MRI radiographies Thing.
- 4. slow-releasing system according to claim 1, it is characterised in thatThe injection aquagel includes the component of following weight percentage：2wt%~10wt% natural polymerses, 0.1wt%~5wt% crosslinking agents；Wherein, the natural polymerses are hyaluronic acid, gelatin；The crosslinking agent is 1, 4- butanediol diepoxy ethers, glutaraldehyde；The w/v of the composite Nano capsule and injection aquagel is 1:3~1:5.The nanocapsule is prepared by polymer base material via emulsion process-solvent evaporation method；Wherein, the polymer base material is that oil-soluble polyphosphazene polymer lactic acid, poly lactic-co-glycolic acid, polylactic acid-polyglycol are common Polymers, polylactic-co-glycolic acid-ethylene glycol copolymer；The medicine of the nanocapsule encapsulating is local anesthetic, CO2 laser weld class medicine, for ultrasound, the medicine of CT or MRI radiographies Thing；Wherein, the local anesthetic is local anesthetics of amide derivatives, including lidocaine, Bupivacaine, mepivacaine, fourth pyrrole card Cause, Etidocaine, prilocaine, ropivacaine；The local anesthetic is esters local anaesthetics, including procaine, chloroprocanine, totokaine, cocaine；The CO2 laser weld class medicine is Basic Fibroblast Growth Factor, nerve growth factor, cranial nerve growthine parenteral solution, first Cobalt amine injection, Pu Lining potassium；It is described be used for ultrasound, the medicine of CT or MRI radiographies is fluorocarbon liquid, Iodic agent, Gd-DTPA and its line style, ring-like more The porphyrin chelate of the more carboxylic class chelates of amine and manganese.
- 5. a kind of composite Nano capsule-injection aquagel dual drug-loading slow-releasing system preparation method, it is characterised in that including as follows Step：Step 1, the composite Nano capsule that entrapped drug is prepared；Step 2, crosslinking agent is added into the solution of high molecular polymer, stirring standing obtains injection aquagel；Step 3, the injection aquagel for obtaining the composite Nano capsule and step 2 that are obtained in step 1 mix, and obtain composite Nano Capsule-injection aquagel dual drug-loading slow-releasing system；Wherein, composite Nano capsule and injection aquagel according to w/v are 1 in step 3:1~1:10 mixing.
- 6. method according to claim 5, it is characterised in thatIn the step 1, the preparation of composite Nano capsule comprises the following steps：Step 1-1, the medicine for needing to encapsulate is dissolved with solvent respectively with polymer base material, ultrasonic emulsification, shape is carried out after mixing Cheng Shui/fat liquor；Step 1-2, the emulsion in step 1-1 is added in the aqueous solution containing emulsifying agent, carries out twice ultrasonic emulsification, obtain Water/oil/water emulsion；Step 1-3, the water obtained in step 1-2/oil/water emulsion is added in the aqueous solution containing emulsifying agent, stirring removes Organic solvent, obtain being encapsulated with the high molecular nanometer capsule aqueous solution of medicine；Step 1-4, the high molecular nanometer capsule aqueous solution of the obtained entrapped drugs of step 1-3 is centrifuged, washing, ultrasonic disperse are cold It is lyophilized dry, obtain composite Nano capsule.
- 7. method according to claim 5, it is characterised in thatIn the step 2, crosslinking agent is BDO diepoxy ether, divinylsulfone, hydrazide compound, in chitosan etc. It is one or more of；In the step 2, the weight percentage of high molecular polymer is 4wt%~20wt% in macromolecule polymer solution； Weight percentage of the crosslinking agent in the solution of high molecular polymer is 0.1wt%~10wt%；In the step 2, stirring dwell temperature is 20 DEG C~50 DEG C；Time is 4~20 hours.
- 8. method according to claim 6, it is characterised in thatIn the step 1-1, polymer-based timber-used organic solvent dissolving；Medicine water or organic solvent dissolving；Wherein, the organic solvent is one kind or several in dichloromethane, chloroform, toluene, acetone, n-hexane or hexamethylene Kind；In the step 1-1, the concentration of polymer base material in organic solvent is 10mg/mL~100mg/mL；Medicine is in solvent In concentration be 1mg/mL~30mg/mL；In the step 1-1, the aqueous phase of water/fat liquor and the volume ratio of oil phase are 1:1~1:10；In the step 1-1, step 1-2, the parameter of ultrasonic emulsification is 50W~300W, and emulsification times are 30s~200s；In the step 1-2, step 1-3, described emulsifying agent is polyvinyl alcohol, polyethylene glycol, Sensor Chip CM 5, chitosan In one or more；In the step 1-2, step 1-3, the weight percentage of emulsifying agent is in the aqueous solution containing emulsifying agent 0.01wt%~10wt%；Concentration of the emulsifying agent in emulsion system is 0.1mg/mL~50mg/mL；In the step 1-4, centrifugation rate is 8000~15000rpm；The freeze-drying temperature is -30 DEG C.
- 9. method according to claim 5, it is characterised in that comprise the following steps：Step 1, the composite Nano capsule that entrapped drug is prepared；Step 2, add isometric weight into the high molecular polymer aqueous solution that weight percentage is 4wt%~20wt% Percentage composition is 0.1wt%~10wt% cross-linking agent aqueous solution, and 4~20 hours are stood after being stirred at 20 DEG C~50 DEG C Obtain injection aquagel；Step 3, by the injection aquagel that the composite Nano capsule and step 2 that are obtained in step 1 obtain it is according to w/v 1:3~1:5 are mixed, and obtain composite Nano capsule-injection aquagel dual drug-loading slow-releasing system；Wherein, in the step 2, crosslinking agent is BDO diepoxy ether, glutaraldehyde.Wherein, in the step 1,When the medicine encapsulated in composite Nano capsule is water soluble drug, the preparation method of composite Nano capsule comprises the following steps：Step 1-1a, the water soluble drug for needing to encapsulate is dissolved with water, polymer-based timber-used organic solvent dissolved, medicine water It is molten it is solidifying mixed with polymer base material organic solution after carry out ultrasonic emulsification, formation water/fat liquor；Step 1-2a, water/fat liquor in step 1-1a is added in the aqueous solution containing emulsifying agent, carries out twice ultrasonic breast Change, obtain water/oil/water emulsion；Step 1-3a, the water obtained in step 1-2a/oil/water emulsion is added in the aqueous solution containing emulsifying agent, stirring removes Organic solvent is removed, obtains being encapsulated with the high molecular nanometer capsule aqueous solution of medicine；Step 1-4a, the high molecular nanometer capsule aqueous solution of the obtained entrapped drugs of step 1-3a is centrifuged, washing, ultrasonic disperse, It is freeze-dried after repeating this centrifugation-cleaning-dispersion process 3~10 times, obtains composite Nano capsule.When the medicine encapsulated in composite Nano capsule is ester soluble drug, the preparation method of composite Nano capsule comprises the following steps：Step 1-1b, the medicine for needing to encapsulate is dissolved with polymer-based timber-used organic solvent, mixed collectively as oil phase with water Ultrasonic emulsification is carried out, forms water/fat liquor；Step 1-2b, water/fat liquor in step 1-1b is added in the aqueous solution containing emulsifying agent, carries out twice ultrasonic breast Change, obtain water/oil/water emulsion；Step 1-3b, the water obtained in step 1-2b/oil/water emulsion is added in the aqueous solution containing emulsifying agent, stirring removes Organic solvent is removed, obtains being encapsulated with the high molecular nanometer capsule aqueous solution of medicine；Step 1-4b, the high molecular nanometer capsule aqueous solution of the obtained entrapped drugs of step 1-3b is centrifuged, washing, ultrasonic disperse, It is freeze-dried after repeating this centrifugation-cleaning-dispersion process 3~10 times, obtains composite Nano capsule.In the step 1-1a, step 1-1b, organic solvent is dichloromethane, chloroform, toluene, acetone, n-hexane or ring One or more in hexane；The concentration of polymer base material in organic solvent is 25~100mg/mL；Concentration of the medicine in water or organic solvent is 5~20mg/mL；The aqueous phase of water/fat liquor and the volume ratio of oil phase are 1:5；In the step 1-1a, step 1-1b, step 1-2a, step 1-2b, the parameter of ultrasonic emulsification is 60~90W, during emulsification Between be 30s；In the step 1-2a, step 1-2b, step 1-3a, step 1-3b, described emulsifying agent is polyvinyl alcohol, poly- second two One or more in alcohol, Sensor Chip CM 5, chitosan；The weight percentage of emulsifying agent is 0.1wt%~4wt% in the aqueous solution containing emulsifying agent；The emulsifying agent exists Concentration in emulsion system is 0.1mg/mL~50mg/mL；In the step 1-4a, step 1-4b, centrifugation rate is 8000~15000rpm；The freeze-drying temperature is -30 DEG C.
- 10. any one of the claim 1-4 composite Nano capsules-injection aquagel dual drug-loading slow-releasing system is used in preparation Purposes in local anaesthesia, CO2 laser weld, radiography related drugs；The local anesthetic related drugs include lidocaine, Bupivacaine, mepivacaine, Bupivacaine, Etidocaine, third Amine cacaine, ropivacaine etc., procaine, chloroprocanine, totokaine, cocaine；The CO2 laser weld class related drugs include Basic Fibroblast Growth Factor, nerve growth factor, cranial nerve growthine note Penetrate liquid, Mecobalamin injection, Pu Lining potassium；The radiography related drugs include fluorocarbon liquid, Iodic agent, Gd-DTPA and its line style, the more carboxylic class chelatings of ring-like polyamines The porphyrin chelate of thing, manganese.
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