CN105708789A - Drug-loaded nanofiber microsphere/hydrogel compound and preparation method and application thereof - Google Patents
Drug-loaded nanofiber microsphere/hydrogel compound and preparation method and application thereof Download PDFInfo
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- CN105708789A CN105708789A CN201610151032.0A CN201610151032A CN105708789A CN 105708789 A CN105708789 A CN 105708789A CN 201610151032 A CN201610151032 A CN 201610151032A CN 105708789 A CN105708789 A CN 105708789A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
Abstract
The invention discloses a drug-loaded nanofiber microsphere/hydrogel compound and a preparation method and application thereof. According to the compound, firstly, polylactic acid-poloxamer F68-polylactic acid multi-block polymer and microtubule inhibition type drugs are made into drug-loaded nanofiber microspheres through a low temperature freezing/phase separation method, and then the drug-loaded nanofiber microspheres are dispersed into hydrogel formed through configuration of the polylactic acid-poloxamer F68-polylactic acid multi-block polymer. The content of the drug-loaded nanofiber microspheres in the compound is 5-35 wt%, the particle size is 20-200 microns, the actual drug loading amount is 7.45-17.32%, and the encapsulation efficiency is 86.64-93.17%; the content of the polylactic acid-poloxamer F68-polylactic acid multi-block polymer in sol is 10 wt% at a minimum, and the sensitivity temperature of the polylactic acid-poloxamer F68-polylactic acid multi-block polymer is greater than or equal to 25 DEG C. By means of the drug-loaded nanofiber microsphere/hydrogel compound and the preparation method and application thereof, the drug amount of the injured part can be increased, acting time is prolonged, the number of drug administration times is remarkably reduced, and the problems of displacement and disintegration of the microspheres at the implantation position can be effectively solved.
Description
Technical field
The invention belongs to pharmaceutical macromolecular material and preparation thereof and applied technical field, be specifically related to a kind of medicament-carrying nano-fiber
Microsphere/hydrogel composites and its preparation method and application.
Background technology
Spinal cord injury has that disability rate is high, case fatality rate is low, the burden on society feature such as heavily, is the medical circle generation being badly in need of at present solving
One of criticality difficult problem.According to incompletely statistics, the whole America has 250000 people to be affected by spinal cord injury, moreover, every year also
13400 examples are had newly to send out spinal cord injury case.Spinal cord injury can be divided into primary injury and two processes of secondary injury.?
During primary injury, because of impairment factor, as spinal column fracture, flexing, rotate, dislocate, compressing etc. can destroy cell
The integrity of film and to cause substantial amounts of flow of calcium ions to enter intracellular, this process triggers and includes inflammation, oxygen-derived free radicals
The a series of Secondary cases biological effects such as release, apoptosis, thus damage is spread to adjacent tissue by initial injury,
Cause the infringement of adjacent tissue.The therapeutic scheme of spinal cord injury includes operative treatment, Drug therapy, rehabilitation etc. at present,
These methods are intended to control the generation of secondary injury, the function of nervous system of protection remaining, but its therapeutic effect all ratios are relatively limited.
The big obstacle of the two of repair of spinal cord injury is formation and the autonomous regeneration capacity of aixs cylinder of body self of fibre modification glial scar
Poor.Having document to report in the recent period, this two big obstacle of repair of spinal cord injury is controlled (Ruschel J, Hellal by microtubule dynamics
F,Flynn KC,et al.Axonal regeneration.Systemic administration of epothilone B promotes axon
regeneration after spinal cord injury.Science.2015；348(6232):347-52.).Growth is converted after spinal cord injury
The expression of the factor-β (TGF-β) dramatically increases, and TGF-β is led by the consideration convey of regulation and control downstream signal factor S mad 2 and promoted
Enter glial scar and form the expression of associated protein such as laminin and fibronectin, thus promote the formation of cicatrix.And spinal cord damages
The cicatrix of position, traumatic part can discharge neuritegrowth inhibitor, promotes the expression of chondroitin sulfate proteoglycan (CSPGs), enters
And suppress axon regeneration.But in normal body, the Smad 2 at spinal cord position can pass through kinesin (Kinesin-1) with micro-
Pipe combines, thus reduces glial scar and form the expression of associated protein.Research finds, low dose of microtubule inhibitors paclitaxel
(trade name: taxol) can make Smad 2 more firm with the combination of micro-pipe, by reducing formation and the promotion of glial scar
The regeneration of aixs cylinder plays effect (Hellal F, Hurtado A, Ruschel J, the et al. promoting repair of spinal cord injury
Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury.
Science.2011；331(6019):928-931).
But, the administering mode that the studies above uses is that the mode of site spinal cord injury in-situ injection drug solution is administered, due to
Pure medicine is very fast at the accretion rate of site spinal cord injury, and bioavailability is low, so that frequent drug administration, thus cause suffering from
Person's compliance is deteriorated, and adds treatment cost.Therefore introduce practice of pharmacy and prepare the medicine with sustained-release and controlled release effect
Transport vehicle, is possible not only to reduce administration number of times, moreover it is possible to improve the bioavailability of medicine, reduces toxic and side effects, and raising is controlled
Therapeutic effect.Degradable medicine carrying microballoons is a kind of application drug delivery system widely, and it is medicine dissolution or is dispersed in
The microscopic, spherical entity formed in macromolecular material substrate, has the advantage that compared with conventional dosage forms (1) can be substantially reduced
Dosage and frequency, improve the compliance of patient；(2) slow-release time is long, when can extend the effect of half-life shorter medicine
Between, make internal blood drug level stable, it is ensured that therapeutic effect；(3) toxic and side effects is little；(4) there is targeting；(5) improve
Medicine stability, protection polypeptide and protein are from acid and the destruction of enzyme.As by medicine carrying microballoons in situ chemotherapy, because having slow release
Effect, can reduce administration number of times, improves curative effect and significantly reduces untoward reaction.
Although microsphere form of administration has plurality of advantages, and belongs to the porous/mesoporous microsphere in macromolecular material class microsphere at present,
Because of features such as its specific surface area are bigger, good stability, controllability strong and surface penetration ability is strong, in material science, biological work
The field such as journey, medical research all has a wide range of applications.And using the salt compounds such as sodium carbonate, sodium bicarbonate as porogen
Pore effect well, but because there being part salt ion to stay in microsphere, so according in the application process of microsphere want
Asking and also need to carry out subsequent treatment, this preparation section to be caused increases, and can't ensure to completely remove [Dai Pingwang,
[J] is probed in the preparation of degradable porous polylactic acid microball. application chemical industry, 2014,43 (3), 449-452.], although ammonium hydrogen carbonate is dividing
Solution preocess can become ammonia and carbon dioxide, the beneficially formation in microsphere hole by Direct Resolution, but mesoporous on the microsphere surface of gained
Actually a kind of minimum Pinhole-shaped structure, and skewness, is also not reaching to run through the effect of whole microsphere.Separately
Outward, though simple PLA homopolymer has higher fusing point and viscosity, but mobility and heat stability are poor, in macromolecular chain not
Containing can reaction active groups, therefore cause that hydrophilic is poor, degradation speed slowly, be unfavorable for that cell sticks at material surface and grows.
And individually employing microsphere is as injection implant transmission system, big owing to being injected into internal microsphere diffusional area, along with body
The reasons such as the motion of body easily cause the problems such as disintegrate and the displacement of microsphere (Jiang Guoqiang, Lin Ying, Sun Jiali, etc..Microsphere/
Thermosensitive hydrogel is combined drug release characteristic and the model [J] of drug delivery implant system. Chinese science and technology paper, 2012,7 (3), 224-229).Collapse
Solve and the existence of shifting phenomena can make the slow control release of microsphere be affected, thus cause the dose of lesions position practical function
Not enough.And the disintegrate being administered initial stage microsphere skeleton will cause the prominent of medicine to release, and medicine prominent is released, and to be likely to result in blood medicine dense
Degree, near or above toxic level, produces obvious toxic and side effects, and phenomenon of burst release can affect the slow releasing agent medicine in the later stage and release
Put speed and deenergized period, it is impossible to reach intended therapeutic effect.(Wang Y,et al.Triblock copolymerF127sustains insulin release and reduces initial burst of microspheres—in vitro and in
vivo study.Colloid Polym Sci(2006)285:233–238.)
Progress in Intelligent Hydrogel is a kind of three-dimensional network that can swell in water significantly but can not dissolve in water or interpenetrating networks,
It can stimulate such as to external world: temperature, pH value, magnetic field, electric field, solvent, light, chemical substance etc. can respond, and produces
Raw discontinuous change in volume.Due to the response of this uniqueness of progress in Intelligent Hydrogel, it is in drug controlled release, sensing
The aspects such as device, memory cell switch, organizational project all have good application prospect (Yu L, Ding JD.Injectable
hydrogels as unique biomedical materials.Chem Soc Rev.2008；37(8):1473-1481).Wherein with biology
Gel prepared by degradability block polymer material, because of its biodegradability and good biocompatibility, more has good
Good development prospect, especially responsive to temperature type gel.This gellike is to link, by non-covalent bond, the physical gel formed,
I.e. reversible gel, it can vary with temperature the transformation of generation glue-molten.Therefore, a lot of researchs are by the degradable medicine carrying microballoons of medicine carrying
It is dispersed in this gel, forms microsphere/gel and be combined medicine-releasing system, effectively to prevent microsphere at the shifting phenomena of injection site
With problem (Lee J, Tan CY, Lee SK, et al.Controlled such as the burst drug releases preventing the disintegrate due to microsphere and cause
delivery of heat shock protein using an injectable microsphere/hydrogel combination system for
the treatment of myocardial infarction[J].Journal of Controlled Release,2009,137(3):196-202；
Wang Y,Gao JQ,Li F,et al.Triblock copolymerF127sustains insulin release and
reduces initial burst of microspheres-in vitro and in vivo study.Colloid Polymer Science,2006,
285(2):233-238)。
For integrated water gel and the advantage of microsphere, Zan is good et al. will be loaded with the poly butyric ester microsphere dispersion of 5-fluorouracil
In chitosan gel rubber, define applicable in-situ injection and implant, and there is the microsphere/gel delivery system (Zan of slow Slow release
Good, Zhu Dequan, Tan Fengping, etc. the heeling-in drug-supplying system .J Tsingh ua Univ under poly butyric ester sustained-release microparticle effect
(Sci&Tech), 2005,45 (9), 1258-1262.)；And Zhao Mingyan et al. has by loading in Sodium Alginate Hydrogel Films
The chitosan microball of control-release function, and by rate of release (Zhao of the degrading and regulating bag load of chitosan somatomedin within it
Name is gorgeous, Li Lihua, and girth is born, Zhou Juguang. the preparation .Progress in of the Sodium Alginate Hydrogel Films of load chitosan microball
Modern Biomedicine.2011,11 (11), 2006-2010.), but because this aquagel degradation speed is fast, and degraded
Speed is difficult to control to, and sodium alginate is the most unstable, all there is serious degraded, Sargassum in addition in production, application process
Acid sodium is the polysaccharose substance of a kind of high polymerization degree, and its gelation is strong, viscosity is big, water solublity is poor, be difficult to be absorbed, because of
This limit sodium alginate many otherwise application (Wu Haige, Zhang Yujuan, Luo Fuwen, etc. sodium alginate degradation bacteria
Screening and the optimization of fermentation condition thereof. food science and technology, 2014,39 (8), 31-36.).
In order to solve above chitosan and the problem of sodium alginate gel existence, CN 101255235B discloses one
PECE, this copolymer is solid or thick liquid under normal operation, and water soluble has
Temperature sensitivity, can use as temperature sensitive hydrogel, but its synthetic method is complicated.First need to be with stannous octoate
For catalyst, and use MPEG to cause caprolactone ring-opening polymerisation 130-150 DEG C of reacting by heating 3～12 hours, obtain
MPEG-PCL diblock copolymer；The different Fo Er of MPEG-PCL diblock copolymer the most again above-mentioned steps prepared
Ketone diisocyanate is made crosslinking coupling agent and is continued reaction 0.5～2 hour, just can obtain PEG-PCL-PEG triblock copolymer
Thing.Due to the most also added with there is the diisocyanate of certain toxicity as crosslinking coupling agent, and the most do not mention how removing
Have virose coupling agent so that it is dangerous that it has certain toxic residue, and synthetic method complexity is also unfavorable for amplifying producing.
Poloxamer (trade name Pluronic) is that the nonionic triblock that a class is made up of polyoxyethylene and polyoxypropylene gathers
Compound (PEO-PPO-PEO), has practicality, biocompatibility, avirulence and reverse multiple drug resistance of tumor (MDR)
Etc. series of advantages.American Pharmacopeia 28 editions record altogether 5 kinds of different sizes poloxamer (124,188,237,338,
407), the emulsifying agent that wherein PLURONICS F87 lists in kind the most abroad as intravenous injection uses, other specification
Poloxamer all has been used for being administered orally or in external preparation.Another triblock polymer with opposite sequence is
PPO-PEO-PPO (trade name Pluronic-R) be also a kind of non-ionic block polymers (25R8,25R4,10R5,
17R4 etc.), it is also widely used for medicine and other fields (Wang QQ, Li L, Jiang SP.Effects of a PPO-PEO-PPO
triblock copolymer on micellization and gelation of a PEO-PPO-PEO triblock copolymer in
aqueous solution.Langmuir 2005,21,9068-9075).But, due to the critical gel of the polymer of poloxamer class
Concentration is higher, even if as trans poloxamer 10R5 therein the most still can not form gel when concentration is more than more than 90%,
Thus use this material to prepare gel and can be greatly increased the usage amount of raw material undoubtedly, thus preparation cost can be greatly increased.Separately
Less due to PPO segment hydrophobicity outward, cause poloxamer to be generally of higher critical micelle concentration, thus also can make it
Easily destroyed after being injected into human body.Therefore using simple poloxamer material is to be difficult to the form with hydrogel and microsphere
Form compound medicine-releasing system.
Summary of the invention
Present invention aim at the deficiency existed for prior art, first provide a kind of medicament-carrying nano-fiber microsphere/hydrogel multiple
The preparation method of compound.
Another object of the present invention is to provide a kind of medicament-carrying nano-fiber prepared by said method microsphere/hydrogel composites.
Another object of the present invention is to provide the application of a kind of above-mentioned medicament-carrying nano-fiber microsphere/hydrogel composites.
The preparation method of medicament-carrying nano-fiber microsphere/hydrogel composites that the present invention provides, the processing step of the method and condition
As follows:
(1) by the polylactic acid-poloxamer F68-polylactic acid multi-block polymer of 46～340 parts with polylactic acid-poloxamer
The mass parts meter 8 of F68-polylactic acid multi-block polymer～micro-pipe suppression class medicine of 20% add 50～70 DEG C, 2500～20000
In part organic solvent, stirring makes it fully dissolve, and obtains settled solution A；By with the stereometer 3 of solution A～the solvent of 6 times
B is preheated to 50～70 DEG C in water-bath, is subsequently adding the stereometer 0.1 by solvent B～the dispersant of 0.3%, forms mixing molten
Liquid C；Under agitation, mixed solvent C is slowly added in settled solution A, after adding, continues stirring 10～30min
Pour in liquid nitrogen, stand 20～40min and obtain frozen material；It is added thereto to >=the frozen water of 1 times of volume with frozen material stereometer
Mixture, carries out with distilled water wash 3～6 times after solvent exchange 24～48h, in less than 20 DEG C preservations after lyophilization, i.e.
Prepare the nanofibrous microsphere of medicine carrying；
(2) polylactic acid-trans poloxamer-polylactic acid multi-block polymer is added by the amount of concentration at least 10wt% after configuration
Enter mix homogeneously in normal saline, then heat to 50～60 DEG C of stirring formation polylactic acid-trans poloxamer-polylactic acid many
Block polymer solution；
(3) by gained medicament-carrying nano-fiber microsphere as 5～30wt% add prepared by polylactic acid-trans poloxamer-poly-
In lactic acid multi-block polymer solution, it is uniformly mixed at 50～60 DEG C, then processes 24h in 4 DEG C.
In above method, polylactic acid-poloxamer F68-polylactic acid (PLA-F68-PLA) the many blocks used by step (1) gather
Compound, its theoretical value average molecular weight is 1.5～3.0 × 104.This multi-block polymer is prepared from by following methods: the party
Method is by L-lactide that mass ratio is 0.786～2.57, poloxamer F68 and according to L-lactide and poloxamer F68
The stannous octoate of gross mass meter 0.3% join in reaction vessel as catalyst, under nitrogen air-flow protection, reactant is added
Heat is to 140-180 DEG C, and 15-24h is reacted in stirring, is cooled to room temperature, then according to the Methods For Purification of routine (Li Ziling, Bears
Xiang Yuan, Gong Yanchun, Li Yuping. the Pluronic P85/ nano polylactic acid particle preparation of embedding paclitaxel and release in vitro behavior
Investigate. Chinese experimental pharmacology of Chinese medical formulae magazine .2014.20,1-4.), i.e. first dissolve reaction gains with dichloromethane, add with two
In the methanol of chloromethanes stereometer 10 times amount, after having whiteness to separate out, filter, after dissolving white depositions with dichloromethane
Place in the ether of in terms of methylene chloride volume 10 times amount, filter, be dried, obtain polylactic acid-poloxamer-polylactic acid many
Block polymer.
In above method, the organic solvent used by step (1) is in chloroform, acetone, ethanol, nitrile or oxolane
At least one, preferably acetone and oxolane.
In above method solvent B used by step (1) be glycerol, relative molecular mass be 200-600 Polyethylene Glycol and
At least one in tetramethylolmethane.
In above method, the micro-pipe suppression class medicine used by step (1) is Docetaxel (Docetaxol, abridge DOC)
Or carbadox match.
In above method, the dispersant used by step (1) is trans poloxamer 10R5 or trans poloxamer 17R4.
Multi-block polymer nanofiber medicine carrying microballoons prepared by step (1) in above method, this microsphere is by nanofiber
The silk hollow microsphere that intertexture is constituted naturally, its particle diameter is 20～200 μm, the nanofibers a diameter of 400～1200 of microsphere surface
Nm, theoretical drug loading is 8～20%, and actual drug loading 7.45～17.32, envelop rate is at least 86.64～93.17%.
In above method, the polylactic acid-trans poloxamer-polylactic acid multi-block polymer used by step (2) is according to lower section
Prepared by method: under inert gas shielding, by L-lactide, trans poloxamer in mass ratio 0.185～1.4 with trans
Poloxamer mixes with the stannous octoate catalyst of the gross mass meter 0.3% of L-lactide, and in 130-160 DEG C of reacting by heating
5-12h, cooling, it is subsequently adding after solvent dissolves reaction gains in the petroleum ether placing into-20 DEG C and precipitates, filter, repeatedly
It is dried after operating 2～3 times, purifies and i.e. obtain polylactic acid-trans poloxamer-polylactic acid multi-block polymer.Wherein, used
Trans poloxamer is trans poloxamer 10R5 (Mn=2000) or trans poloxamer 17R4 (Mn=2700), the most instead
Formula poloxamer 10R5, and the mass ratio of L-lactide and trans poloxamer 10R5 is 0.25～1.4, L-lactide with
The mass ratio of trans poloxamer 17R4 is 0.185～1.185；Concrete method of purification used is: by molten for dry gains
In deionized water, bag filter dialysis is then used to remove small molecule monomer and the catalyst of excess, institute's block much after dialysis
Polymers freeze seals preservation after drying.
The reason of polylactic acid-trans poloxamer 10R5-polylactic acid multi-block polymer obtained by step (2) in above method
Opinion number-average molecular weight is 2.5～4.8 × 103, obtained polylactic acid-trans poloxamer 17R4-polylactic acid multi-block polymer
Theoretical value average molecular weight be 3.2～5.9 × 103。
In above method, the polylactic acid-trans poloxamer-polylactic acid multi-block polymer solution obtained by step (2) forms water
The critical gel strength (CGC) preferably 10～50wt% of gel, more preferably 10～35wt%, critical gelling temp (CGC)
It it is 25～35 DEG C.
The medicament-carrying nano-fiber prepared by said method microsphere/hydrogel composites that the present invention provides, this complex is by colloidal sol
With the medicament-carrying nano-fiber microsphere composition being uniformly distributed therein, the content of medicament-carrying nano-fiber microsphere is 5～35wt%, should
Microsphere is the hollow microsphere constituted that naturally interweaved by nanofibers, and its particle diameter is 20～200 μm, and theoretical drug loading is
8～20%, actual drug loading is 7.45～17.32%, and envelop rate is 86.64～93.17%；In colloidal sol, polylactic acid-trans pool Lip river is husky
The content at least 10wt% of nurse-polylactic acid multi-block polymer, preferably 10～50wt%, more preferably 10～35wt%, it is quick
Temperature-sensitive degree >=25 DEG C, preferably 25～35 DEG C.
The application of medicament-carrying nano-fiber microsphere/hydrogel composites that the present invention provides is being repaired for acute spinal cord injury
Application.
The present invention compared with prior art, has the advantage that
1, due to the present invention will be loaded with treat acute spinal cord injury repair medicine micro-pipe suppression class medicine nanofiber micro-
Ball is creatively combined in one with the polylactic acid-trans poloxamer-polylactic acid multi-block polymer solution that can form hydrogel
Rise, be prepared for a kind of medicament-carrying nano-fiber microsphere/hydrogel composites, this complex can direct injection in site spinal cord injury,
Carry out regional sustained-release chemotherapy, thus damage location medication amount not only can be made to increase, extended durations of action, substantially reduce administration
Number of times, and the problem that can effectively solve displacement that microsphere exists at implant site and disintegrate.
2, due to the present invention provide complex in nanofibrous microsphere be with multi-block polymer PLA-F68-PLA as base
Body material, the method using freezing/separated, prepare under conditions of surfactant-free exists, not only make
Preparation Method is simple, and the nanofibrous microsphere of gained is the hollow microsphere constituted that naturally interweaved by nanofibers, specific surface area
Greatly, by increasing capacitance it is possible to increase the medicine dispersed degree in microsphere nano fiber shell, clad ratio is high, can effectively control medicine
Release, reduces toxic and side effects, reaches good therapeutic effect.
3, due to the present invention provide complex in hydrogel be how embedding by PLA-10R5-PLA or PLA-17R4-PLA
Temperature sensitive hydrogel prepared by section polymer, it not only can increase the intensity of gel, it is possible to convenient use, adds that it is raw
The thing compatibility is good, can degrade the most voluntarily, thus not only has good biological safety, and also changes poloxamer
The critical gel strength of the polymer of class is higher, even can not form the situation of gel.
4, nanofibrous microsphere/gel composite of preparing due to the present invention can be to preserve after lyophilizing, to prepare in powder form
Gel need not use the excellent features such as cross-linking agent, therefore at drug release control system and biological medical polymer material etc.
Application has fabulous application prospect.
5, easy and simple to handle due to the inventive method, efficiency of pcr product is high, gel strength is adjustable, good biocompatibility, is applicable to
Large-scale production.
Accompanying drawing explanation
Fig. 1 is the scanning electron microscope (SEM) photograph of the PLA-F68-PLA nanofibrous microsphere prepared by embodiment 4.Show the nanometer of preparation
The surface of fiber microsphere all presents the netted structure of nanofiber, and size is about 50 μm.
The scanning electron microscope (SEM) photograph of the nanofibrous microsphere prepared by Fig. 2 embodiment 13/hydrogel compound system lyophilized powder.From figure
Can be seen that nanofibrous microsphere is uniformly embedded in hydrogel, structural integrity.
Fig. 3 is prepared Mn=4.0 × 103The FTIR collection of illustrative plates of PLA-10R5-PLA multi-block polymer.In figure
1750cm-1And 600-800cm-1The absworption peak at place, illustrates the successful synthesis of multi-block polymer.
Fig. 4 is prepared Mn=4.0 × 103PLA-10R5-PLA multi-block polymer1H NMR spectra.In figure
Peak at 5.20ppm represents CH (CH in PLA segment3) hydrogen atom in CO methine, at 3.35-3.70ppm
Peak represents OCH in Pluronic segment2–CH2And OCH2–CH(CH3The hydrogen atom in methylene in),
4.3-4.4ppm the peak at place represents PLA-CO-OCH2-CH2Hydrogen atom in-O-Pluronic fragment methylene.The most also
Demonstrate the successful synthesis of multi-block polymer.
Fig. 5 is prepared Mn=4.0 × 103The gpc chromatogram of PLA-10R5-PLA multi-block polymer.Result records
MwcIt is 6.12 × 103, MncIt is 4.92 × 103。
Fig. 6 is the DSC collection of illustrative plates of 10R5 (a) and prepared PLA-10R5-PLA multi-block polymer (b).From figure
In it can be seen that the melting peak of 10R5 is positioned at-22 DEG C, the melting peak of PLA-10R5-PLA multi-block polymer is then positioned at
About 70 DEG C.Illustrating that the melt temperature of the 10R5 after PLA modification raises, heat stability improves.
Fig. 7 is the XRD figure spectrum of each sample.Wherein A is Docetaxel, and B is the many block polymerizations of PLA-F68-PLA
Thing blank microsphere, C is the nanofibrous microsphere containing 15% (w/w) Docetaxel, and D is purple containing 15% (w/w) polyenoid
The nanofibrous microsphere of China fir alcohol/hydrogel compound system.As can be seen from the figure 15% (w/w) Docetaxel and poly-breast are contained
The XRD curve of acid-poloxamer F68-polylactic acid multi-block polymer has the diffraction maximum of Docetaxel, and is containing
15% (w/w) Docetaxel/polylactic acid-poloxamer F68-polylactic acid multi-block polymer nanofiber medicine carrying microballoons
XRD curve then be can't see, illustrate that medicine is to be loaded in nanofibrous microsphere with amorphous form.
Fig. 8 is the FTIR collection of illustrative plates of each sample.Wherein A is Docetaxel, and B is the many block polymerizations of PLA-F68-PLA
Thing blank microsphere, C is the nanofibrous microsphere containing 15% (w/w) Docetaxel, and D is purple containing 15% (w/w) polyenoid
The nanofibrous microsphere of China fir alcohol/hydrogel compound system.From collection of illustrative plates, at 680-800cm-1Position, compared with curve B,
Curve C and D emerging tiny characteristic absworption peak, just at 680-800cm in homologous thread A-1Position feature absworption peak,
Illustrate that medicine is the most successfully loaded in nanofibrous microsphere.
Fig. 9 is the drug release in vitro curve of each sample.Wherein a is the release profiles of free Docetaxel, and b is nanometer
The release profiles of fiber microsphere Docetaxel, c is the release of Docetaxel in nanofibrous microsphere/hydrogel compound system
Curve.As can be seen from the figure the rate of release of the DOC in nanofiber medicine carrying microballoons relatively dissociate DOC rate of release show
Work slows down, and illustrates that this nanofiber medicine carrying microballoons has obvious slow release effect.And nanofibrous microsphere/hydrogel complex
In system, the rate of release of the Docetaxel rate of release compared with the DOC in nanofiber medicine carrying microballoons is slow.
Figure 10 be embodiment 13 preparation carrying docetaxel nanofibrous microsphere/hydrogel compound system at different temperatures
Apparent state, it can be seen that this compound system is its gel state when 37 DEG C, be collosol state when 4 DEG C.
Figure 11 is the BBB scoring that different time points respectively organizes Model of Rat Spinal Cord Injury, and wherein a is receiving of carrying docetaxel
Rice fiber microsphere/hydrogel compound system group, b be PLA-10R5-PLA hydrogel group, c be the nanometer of carrying docetaxel
Fiber microsphere group, d be normal saline group, e be sham operated rats.It can be seen that in addition to postoperative 1 day, remaining time
Between point be loaded with Docetaxel nanofibrous microsphere/hydrogel compound system group BBB mark apparently higher than other each group,
Illustrate that this medicine-carried system is conducive to acute spinal cord injury reparation.
Figure 12 is the HE dyeing that different time points respectively organizes Model of Rat Spinal Cord Injury.Wherein a is sham operated rats, and b is load
The nanofibrous microsphere of Docetaxel/hydrogel compound system group, c are PLA-10R5-PLA multi-block polymer hydrogel
Group, d be load the nanofibrous microsphere group of Docetaxel, e be normal saline group.It can be seen that except sham-operation
Outside group, remaining each treatment group all has white matter in various degree, the destruction of grey matter integrity at each time point, but load polyenoid is purple
The nanofibrous microsphere of China fir alcohol/hydrogel compound system group is good compared with other treatment group at white matter, the grey matter integrity of each time point,
Glial scar is also significantly less than other treatment group.
Figure 13 is the magnetic resonance photo before and after the treatment of rat half cross-section spinal cord injury model.
Figure 14 is the major organs HE stained of rat, wherein A-E be respectively the heart of normal saline group, liver, spleen, lung,
Kidney；F-J is the load nanofibrous microsphere/heart of hydrogel compound system group of Docetaxel, liver, spleen, lung, kidney.From
In figure it can be seen that give load Docetaxel nanofibrous microsphere/hydrogel compound system after each main organs of rat not
See obvious pathological changes.Illustrate that the nanofibrous microsphere/hydrogel compound system of the load Docetaxel used in the present invention is at body
Interior application is nontoxic for main organs.
Detailed description of the invention
Embodiment is given below be described in further detail with the foregoing to the present invention.But this should be interpreted as this
The scope of bright above-mentioned theme is only limitted to below example.Without departing from the idea case in the present invention described above, according to ability
Various replacements that territory ordinary technical knowledge and customary means are made or change, be included within the scope of the present invention.
What deserves to be explained is: 1) poloxamer used in following example: poloxamer188, is called for short F68；
R [(PPO) 8 (PEO) 22 (PPO) 8], is called for short 10R5, R [(PPO) 14 (PEO) 24 (PPO) 14], is called for short 17R4.2) below
Multi-block polymer prepared in embodiment: polylactic acid-Pluronic F68-polylactic acid, is called for short PLA-F68-PLA；Poly-breast
Acid-R [(PPO) 8 (PEO) 22 (PPO) 8]-polylactic acid, is called for short PLA-10R5-PLA.Polylactic acid
-R [(PPO) 14 (PEO) 24 (PPO) 14]-polylactic acid, is called for short PLA-17R4-PLA.3) polylactic acid of following example gained-
Poloxamer-polylactic acid multi-block polymer and the weight average molecular weight (Mw of polylactic acid-trans poloxamer-polylactic acidc) sum
Average molecular weight (Mnc) use chromatograph of gel permeation (GPC) method to record, MnbIt it is basis1H-NMR calculates
Gained, MnaIt it is then the theoretical value calculated according to rate of charge.4) mensuration of following example gained medicine carrying microballoons particle diameter is to use
Malvern laser particle analyzer (Malvern 2000, Malvern Instr Ltd., Britain).5) many blocks in following example
In polymer nanofiber medicine carrying microballoons, the mensuration of drug loading is to use RP-HPLC method to measure, and detection wavelength is
230nm, flowing is acetonitrile mutually: water (50:50).6) drug loading and the envelop rate of following example thus obtained microsphere is by following
Formula calculates:
Actual drug loading=nanofiber medicine carrying microballoons Chinese medicine amount/nanofiber medicine carrying microballoons total amount × 100%
Envelop rate=nanofiber medicine carrying microballoons Chinese medicine amount/dosage × 100%
Main agents used by the embodiment of the present invention and instrument:
DL-lactide (DL-LA), L-lactide (L-LA) is purchased from Guangshui, Hubei Chemical Co., Ltd. of nationality
Poloxamer188 (F68, Mn=8400), R [(PPO) 8 (PEO) 22 (PPO) 8] (10R5, Mn=2000,
WPEG%=50%) purchased from Sigma-Aldrich, analytical pure.
Stannous octoate (Stannous octoate, Sn (oct)2), purchased from Sigma-Aldrich, analytical pure.
The brief synthetic route of PLA-F68-PLA multi-block polymer of the present invention is as follows:
Embodiment 1
Under nitrogen air-flow protection, by L-lactide that mass ratio is 2.57, poloxamer F68 and according to L-lactide and pool
The gross mass meter 0.3wt% stannous octoate of Luo Shamu is heated to 180 DEG C of stirring reaction 24h, is cooled to room temperature, is subsequently adding two
Reaction gains are dissolved by chloromethanes, place in the methanol of in terms of methylene chloride volume 10 times amount and precipitate, filter, use dichloro
Put into continuation in the ether of in terms of methylene chloride volume 10 times amount after methane dissolving white depositions to precipitate, filter, be dried,
Obtain theoretical molecular MnaIt is 3.0 × 104Polylactic acid-poloxamer F68-polylactic acid multi-block polymer.Calculated by nuclear-magnetism
MnbIt is 2.85 × 104, GPC result records MwcIt is 4.23 × 104, MncIt is 3.02 × 104。
Embodiment 2
Under nitrogen air-flow protection, by L-lactide that mass ratio is 0.786, poloxamer F68 and according to L-lactide and pool
The gross mass meter 0.3wt% stannous octoate of Luo Shamu is heated to 150 DEG C of stirring reaction 15h, is cooled to room temperature, is subsequently adding two
Reaction gains are dissolved by chloromethanes, place in the methanol of in terms of methylene chloride volume 10 times amount and precipitate, filter, use dichloro
Put into continuation in the ether of in terms of methylene chloride volume 10 times amount after methane dissolving white depositions to precipitate, filter, be dried,
Obtain theoretical molecular MnaIt is 1.5 × 104Polylactic acid-poloxamer F68-polylactic acid multi-block polymer.Calculated by nuclear-magnetism
MnbIt is 1.36 × 104, GPC result records MwcIt is 2.30 × 104, MncIt is 1.52 × 104。
Embodiment 3
According to said synthesis route, under nitrogen air-flow protection, by L-lactide that mass ratio is 1.38, poloxamer F68
It is heated to 140 DEG C of stirring reaction 20h, cooling with according to the gross mass meter 0.3wt% stannous octoate of poloxamer Yu L-lactide
To room temperature, it is subsequently adding dichloromethane and reaction gains are dissolved, place in the methanol of in terms of methylene chloride volume 10 times amount
Precipitation, filtration, put into after dissolving white depositions with dichloromethane in the ether of in terms of methylene chloride volume 10 times amount and continue
Precipitate, filter, be dried, obtain theoretical molecular MnaIt is 2.5 × 104Polylactic acid-many blocks of poloxamer F68-polylactic acid gather
Compound.The Mn calculated by nuclear-magnetismbIt is 2.56 × 104, GPC result records MwcIt is 3.74 × 104, MncIt is 2.38 × 104。
Embodiment 4
By the polylactic acid obtained by 46 parts of embodiments 2-poloxamer F68-polylactic acid multi-block polymer with in terms of its quality
The Docetaxel of 8% adds in the mixed organic solvents of 50 DEG C, 2500 parts of acetone and oxolane (1:1, v/v), stirring
Make it fully dissolve, obtain settled solution A；First by the glycerol of the stereometer 3 times with solution A and tetramethylolmethane (2:1,
V/v) the mixed solvent B formed is preheated to 50 DEG C in water-bath, is subsequently adding the dispersant by the stereometer 0.1% of solvent B
17R4, forms mixed solvent C；Under agitation, the mixed solvent C of preheating is slowly added in settled solution A,
Continue stirring 10min after adding and pour in liquid nitrogen, stand 20min and obtain frozen material；Add wherein with frozen material stereometer
Enter >=the mixture of ice and water of 1 times of volume, carry out with distilled water wash 3～6 times after solvent exchange 24h, in 20 after lyophilization
Preserve below DEG C.
The particle diameter of gained nanofiber medicine carrying microballoons is 50～150 μm, a diameter of the 500 of the nanofibers on surface～1000nm；
Actual drug loading is 7.45 ± 0.15%, and envelop rate is 93.17 ± 1.88%.
The present invention first the nanofiber medicine carrying microballoons of the present embodiment gained has been carried out scanning electron microscope (SEM) (JSM-5900LV,
JEOL, Tokyo, Japan) to observe, result is shown in Fig. 1.It can be seen from figure 1 that the surface of the nanofibrous microsphere of preparation all presents
The netted structure of nanofiber, size is about 50 μm, and there is the hole of an opening one end of this nanofibrous microsphere, in
Existing hollow structure.Next uses X-ray diffraction (XRD) (X ' Pert Pro MPD DY1291, PHILIPS, Netherlands)
To medicine, blank nanofibrous microsphere and medicament-carrying nano-fiber microsphere are analyzed, and result is as shown in Figure 7.Can from this figure
Seeing, after medicine is loaded in nanofibrous microsphere inside, the peak crystallization of medicine weakens and even disappears, and illustrates that medicine is with without fixed
The form of kenel is wrapped in inside microsphere..
Embodiment 5
By the polylactic acid obtained by 135 parts of embodiments 1-poloxamer F68-polylactic acid multi-block polymer with in terms of its quality
The Docetaxel of 10% adds in the mixed organic solvents of 55 DEG C, 7500 parts of chloroform and oxolane (1:2, v/v),
Stirring makes it fully dissolve, and obtains settled solution A；First by the Polyethylene Glycol (Mn=200) of the stereometer 5 times with solution A
Solvent B is preheated to 55 DEG C in water-bath, is subsequently adding the dispersant 10R5 by the stereometer 0.3% of solvent B, forms mixing
Solvent C；Under agitation, the mixed solvent C of preheating is slowly added in settled solution A, after adding, continues stirring
20min pours in liquid nitrogen, stands 30min and obtains frozen material；It is added thereto to >=the ice of 1 times of volume with frozen material stereometer
Aqueous mixtures, carries out with distilled water wash 3～6 times after solvent exchange 36h, in less than 20 DEG C preservations after lyophilization.
The particle diameter of gained nanofiber medicine carrying microballoons is 75～200 μm, a diameter of the 700～1100 of the nanofibers on surface
nm；Actual drug loading is 8.91 ± 0.30%, and envelop rate is 88.94 ± 3.02%.
Embodiment 6
By the polylactic acid obtained by 340 parts of embodiments 1-poloxamer F68-polylactic acid multi-block polymer with its mass parts
In the Docetaxel addition 65 DEG C of meter 15%, 20000 parts of oxolane organic solvents, stirring makes it fully dissolve, and obtains
Settled solution A；First the glycerol solvent B of the stereometer 6 times with solution A is preheated to 65 DEG C in water-bath, then adds
Enter the dispersant 17R4 by the stereometer 0.3% of solvent B, form mixed solvent C；Under agitation, mixing preheating
Bonding solvent C is slowly added in settled solution A, continues stirring 20min and pours in liquid nitrogen, stand 40min and obtain after adding
To frozen material；It is added thereto to >=the mixture of ice and water of 1 times of volume, with steaming after carrying out solvent exchange 48h with frozen material stereometer
Distilled water is washed 3～6 times, in less than 20 DEG C preservations after lyophilization.
The particle diameter of gained nanofiber medicine carrying microballoons is 40～150 μm, a diameter of the 400 of the nanofibers on surface～900nm；
Actual drug loading is 13.06 ± 0.71%, and envelop rate is 87.04 ± 4.77%.
Embodiment 7
By the polylactic acid obtained by 200 parts of embodiments 3-poloxamer F68-polylactic acid multi-block polymer with its mass parts
The Cabazitaxel of meter 20% adds 70 DEG C, in 12000 parts of acetonitrile organic solvents, and stirring makes it fully dissolve, and obtains clarifying molten
Liquid A；First by the Polyethylene Glycol (Mn=400) of the stereometer 6 times with solution A and glycerol (1:1, v/v) solvent B in
Water-bath is preheated to 70 DEG C, is subsequently adding the dispersant 10R5 by the stereometer 0.2% of solvent B, form mixed solvent C；
Under agitation, the mixed solvent C of preheating is slowly added in settled solution A, after adding, continues stirring 30min
Pour in liquid nitrogen, stand 40min and obtain frozen material；It is added thereto to >=the frozen water of 1 times of volume mixing with frozen material stereometer
Thing, carries out with distilled water wash 3～6 times after solvent exchange 48h, in less than 20 DEG C preservations after lyophilization.
The particle diameter of gained nanofiber medicine carrying microballoons is 20～160 μm, a diameter of the 600～1200 of the nanofibers on surface
nm；Actual drug loading is 13.06 ± 0.71%, and envelop rate is 86.64 ± 5.12%.
The brief synthetic route of PLA-10R5-PLA and PLA-17R4-PLA multi-block polymer of the present invention is as follows:
Embodiment 8
By the L-lactide that mass ratio is 1,10R5 and according to L-lactide and the stannous octoate of 10R5 gross mass meter 0.3%
For catalyst, under nitrogen protection, stirring is warming up to 140 DEG C, after reacting 10h hour, is cooled to room temperature, adds dichloro
Methane dissolves reaction gains, precipitates in the petroleum ether of-20 DEG C, filters, and after repeatable operation 2～3 times, is dried.By above-mentioned
PLA-10R5-PLA is dried gains and is dissolved in deionized water, uses bag filter dialysis to remove urging of small molecule monomer and excess
Agent.Seal after multi-block polymer lyophilization after dialysis and preserve.
I.e. obtain theoretical molecular MnaIt is 4.0 × 103PLA-10R5-PLA multi-block polymer.
The present invention to the nanofiber medicine carrying microballoons of the present embodiment gained with Fourier infrared spectrograph (Nicolet 6700,
Thermo), using KBr pressed disc method that the multi-block polymer of synthesis is carried out infrared spectrum (FTIR) and analyze, result is shown in figure
3,1750cm in figure-1And 600-800cm-1The absworption peak that place presents, illustrates L1400-R2000-L1400The one-tenth of multi-block polymer
Merit synthesizes；Also use nuclear magnetic resonance analyser (BRUKER AVANCE III400, BRUKER), under the conditions of 400MHZ,
With CDCl3For solvent, with tetramethylsilane as internal standard, the multi-block polymer of synthesis is carried out magnetic resonance spectroscopy (1H-NMR)
Analyzing, result is shown in Fig. 4.In Fig. 4, the peak at 5.20ppm represents CH (CH in PLA segment3) in CO methine
Hydrogen atom, the peak at 3.35-3.70ppm represents OCH in Pluronic segment2–CH2And OCH2–CH(CH3Asia in)
Hydrogen atom in methyl, the peak at 4.3-4.4ppm represents PLA-CO-OCH2-CH2In-O-Pluronic fragment methylene
Hydrogen atom.Thus also demonstrate L1400-R2000-L1400The successful synthesis of multi-block polymer.The most also calculated by nuclear-magnetism
MnbIt is 4.02 × 103, recorded Mw by (see Fig. 5) result of GPC againcIt is 6.12 × 103, MncIt is 4.92 × 103。
The most also investigate by differential scanning calorimetry (DSC) (Netzsch 204, Netzsch Corp., Germany)
The hot property of PLA-10R5-PLA, is shown in Fig. 6.From fig. 6, it can be seen that the melting peak of 10R5 is about-23 DEG C.And
The melting peak of PLA-10R5-PLA then increases about 70 DEG C.
Embodiment 9
By L-lactide, 10R5 and the octanoic acid Asia according to L-lactide and 10R5 gross mass meter 0.3% that mass ratio is 0.25
Stannum is catalyst, and under nitrogen protection, stirring is warming up to 130 DEG C, after reacting 7h hour, is cooled to room temperature, adds tetrahydrochysene
Furan dissolves reaction gains, precipitates in the petroleum ether of-20 DEG C, filters, repeatable operation 2～3 times, is dried.By above-mentioned
PLA-10R5-PLA is dried gains and is dissolved in deionized water, uses bag filter dialysis to remove urging of small molecule monomer and excess
Agent.Seal after multi-block polymer lyophilization after dialysis and preserve.
The theoretical molecular Mn of obtained multi-block polymeraIt is 2.5 × 103PLA-10R5-PLA.Additionally by nuclear-magnetism meter
The Mn calculatedbIt is 2.66 × 103, GPC result records MwcIt is 3.76 × 103, MncIt is 2.59 × 103。
Embodiment 10
By the L-lactide that mass ratio is 1.4,10R5 and according to L-lactide and the stannous octoate of 10R5 gross mass meter 0.3%
For catalyst, under nitrogen protection, stirring is warming up to 150 DEG C, after reacting 12h hour, is cooled to room temperature, adds trichlorine
Methane dissolves reaction gains, precipitates in the petroleum ether of-20 DEG C, filters, repeatable operation 2～3 times, is dried.By above-mentioned
PLA-10R5-PLA is dried gains and is dissolved in deionized water, uses bag filter dialysis to remove urging of small molecule monomer and excess
Agent.Seal after multi-block polymer lyophilization after dialysis and preserve.
The theoretical molecular Mn of obtained multi-block polymeraIt is 4.8 × 103PLA-10R5-PLA multi-block polymer.
The Mn additionally calculated by nuclear-magnetismbIt is 4.76 × 103, GPC result records MwcIt is 6.12 × 103, MncIt is 4.92 × 103。
Embodiment 11
By the L-lactide that mass ratio is 0.185,17R4 and the octanoic acid Asia according to L-lactide and 17R4 gross mass meter 0.3%
Stannum is catalyst, and under nitrogen protection, stirring is warming up to 145 DEG C, after reacting 5h hour, is cooled to room temperature, adds trichlorine
Methane and oxolane (1:2, v:v) dissolve reaction gains, precipitate in the petroleum ether of-20 DEG C, filter, repeatable operation
2～3 times, it is dried.Above-mentioned PLA-17R4-PLA is dried gains be dissolved in deionized water, uses bag filter dialysis to remove
Small molecule monomer and the catalyst of excess.Seal after multi-block polymer lyophilization after dialysis and preserve.
The theoretical molecular Mn of obtained multi-block polymeraIt is 3.2 × 103PLA-17R4-PLA multi-block polymer.
The Mn additionally calculated by nuclear-magnetismbIt is 3.42 × 103, GPC result records MwcIt is 4.56 × 103, MncIt is 3.37 × 103。
Embodiment 12
By the L-lactide that mass ratio is 1.185,17R4 and the octanoic acid Asia according to L-lactide and 17R4 gross mass meter 0.3%
Stannum is catalyst, and under nitrogen protection, stirring is warming up to 160 DEG C, after reacting 12h hour, is cooled to room temperature, adds two
Chloromethanes and chloroform (3:1, v:v) dissolve reaction gains, precipitate in the petroleum ether of-20 DEG C, filter, repeatedly grasp
Make 2～3 times, be dried.Above-mentioned PLA-17R4-PLA is dried gains be dissolved in deionized water, uses bag filter dialysis to remove
Remove the catalyst of small molecule monomer and excess.Seal after multi-block polymer lyophilization after dialysis and preserve.
The theoretical molecular Mn of obtained multi-block polymeraIt is 5.9 × 103PLA-17R4-PLA multi-block polymer.
The Mn additionally calculated by nuclear-magnetismbIt is 5.78 × 103, GPC result records MwcIt is 7.76 × 103, MncIt is 5.69 × 103。
Embodiment 13
PLA-10R5-PLA multi-block polymer embodiment 7 prepared adds physiology salt by the amount of concentration 25wt% after configuration
Mix homogeneously in water, then heats to 50 DEG C of stirrings and forms solution, in 4 DEG C, gained solution is processed 24h and can be used as water-setting
Glue uses.Hydrogel aperture less for 1 micron, bigger for 20 microns.Hydrogel prepared by above-mentioned steps and enforcement
The nanofibrous microsphere of example 6 preparation, at 50 DEG C, is 15% according to nanofibrous microsphere and hydrogel mass ratio, under agitation
Mix homogeneously, processes 24h by gained solution in 4 DEG C and can be used as nanofibrous microsphere/hydrogel composites use.
Figure 10 is that microsphere/hydrogel compound system is at 4 DEG C and the photo of 37 DEG C.It appeared that when temperature less than body temperature (such as 4
DEG C) time, multi-block polymer aqueous solution presents pellucidity, has mobility；When temperature is 37 DEG C, many block polymerizations
Thing aqueous solution shows transparent solid shape, loses flowability.The change of temperature can make this complex Gel-sol transition occur.
Embodiment 14
PLA-10R5-PLA multi-block polymer embodiment 8 prepared adds physiology salt by the amount of concentration 50wt% after configuration
Mix homogeneously in water, then heats to 50 DEG C of stirrings and forms solution, in 4 DEG C, gained solution is processed 24h and can be used as water-setting
Glue uses.Hydrogel aperture less for 1 micron, bigger for 20 microns.Hydrogel prepared by above-mentioned steps and enforcement
The nanofibrous microsphere of example 4 preparation, at 50 DEG C, according to nanofibrous microsphere and hydrogel mass ratio 35%, under agitation mixes
Close uniformly, gained solution is processed 24h in 4 DEG C and can be used as nanofibrous microsphere/hydrogel composites use.
Embodiment 15
PLA-10R5-PLA multi-block polymer embodiment 8 prepared adds physiology salt by the amount of concentration 10wt% after configuration
Mix homogeneously in water, then heats to 60 DEG C of stirrings and forms solution, in 4 DEG C, gained solution is processed 24h and can be used as water-setting
Glue uses.Hydrogel aperture less for 4 microns, bigger for 30 microns.Hydrogel prepared by above-mentioned steps and enforcement
The nanofibrous microsphere of example 7 preparation, at 60 DEG C, according to nanofibrous microsphere and hydrogel mass ratio 5%, under agitation mixes
Close uniformly, gained solution is processed 24h in 4 DEG C and can be used as nanofibrous microsphere/hydrogel composites use.
Embodiment 16
PLA-10R5-PLA multi-block polymer embodiment 8 prepared adds normal saline by the amount of concentration 35wt% after configuration
Middle mix homogeneously, then heats to 55 DEG C of stirrings and forms solution, in 4 DEG C, gained solution is processed 24h and can be used as hydrogel
Use.Hydrogel aperture less for 2 microns, bigger for 25 microns.Hydrogel prepared by above-mentioned steps and embodiment
The nanofibrous microsphere of 5 preparations, at 55 DEG C, according to nanofibrous microsphere and hydrogel mass ratio 20%, under agitation mixes
Uniformly, gained solution is processed 24h in 4 DEG C and can be used as nanofibrous microsphere/hydrogel composites use.
Embodiment 17
Take PLA-10R5-PLA and medicament-carrying nano-fiber microsphere in 10ml test tube, at 50 DEG C, be configured to 40g/100ml's
Aqueous solution, volume is 2ml, system temperature is down to 37 DEG C and forms gel；Then in test tube, add pH=7.4, temperature
The phosphate buffered solution of 37 DEG C, the release behavior of detection medicine, result is shown in Fig. 9.Fig. 9 lists the external of medicine release
Let pass as curve.The result of this embodiment shows that medicine can slowly discharge in this compound system.
Application examples
Should use-case be medicament-carrying nano-fiber microsphere/hydrogel compound system to be used for internal acute spinal cord injury repairing effect in fact
Test
Should use-case be that medicament-carrying nano-fiber microsphere/hydrogel compound system is for SD rat spinal cord half cross-section model Experiment on therapy
Effect assessment.With Mn for 3.0 × 104The nanofibrous microsphere prepared of PLA-F68-PLA be 4.0 × 10 with Mn3
PLA-10R5-PLA multi-block polymer 25% aqueous solution compound system as a example by.
Concrete grammar is first to prepare medicament-carrying nano-fiber microsphere and nanofibrous microsphere/water-setting according to embodiment 6 and embodiment 13
Glue compound system, rat spinal cord half cross-section model construction Post operation and Post operation 15 days, be administered in situ at site spinal cord injury,
After treatment certain time, therapeutic effect is evaluated.
A. the foundation of the cross-section model of rat spinal cord half
10% chloral hydrate (0.3ml/100g) intraperitoneal injection of anesthesia rat, chest and back field of operation preserved skin, sterilization, ventricumbent position
Be fixed on plank, by chest and back spinous process the most substantially locate to do centered by (about breast 9,10 sections) one be about 3 centimetres after hit exactly
Otch, blunt separation bilateral subcutaneous tissue and paraspinal muscle, appear T9-T10 spinous process, vertebral plate and transverse process, sting except breast 9,10
Spinous process, carefully stings except breast 10 bilateral lamina at breast 10,11 lamina gap, spinal cord is completely exposed, and sharp knife sheet is perpendicular to ridge
Spinal meninges on the right side of marrow incision, spring shears is close to the cross-section spinal cord of posterior spinal artery half.Hereafter rat is randomized into 5 groups and (often organizes 18
Only): sham operated rats, normal saline group (control), PLA-10R5-PLA hydrogel group, the nanometer of load Docetaxel
Fiber microsphere, the nanofibrous microsphere/hydrogel compound system group of load Docetaxel.
B. half cross-section repair of spinal cord injury effect assessment
The nanofibrous microsphere of load Docetaxel, the nanofibrous microsphere/hydrogel compound system group of load Docetaxel
When being administered, DOC amount is 1.8 μ g every time, is administered in Post operation and 15 days after operation, twice totally.Use BBB (Basson Beattle
Bresnaha) motor function scores method (BBB motor function appraisement system be nineteen ninety-five by Basson, Beattle and
Bresnahan proposes a kind of new evaluation system with the 3 people named BBB of surname initial letter, after being exclusively used in evaluation spinal cord injury
The recovery situation of hind leg functional status), preoperative 1d and postoperative 1,7,14,21,28 days and March respectively to each experiment
Group rat motor function is marked.BBB point system is according to animal hip, knee joint, ankle, toe, the situation such as limb coordination exercise front and back
Evaluation motor function, divides 22 grades, the highest 21 points, panplegia 0 point.Scoring process is commented morning 9 successively double blinding by two people
Point, observing time is 5 minutes, the result average out to final result of two people.Rat hindlimb motion BBB neurological deficit score standard
Such as following table.
Postoperative 7,14,28 days, March, sacrificing and put to death rat, concrete grammar is as follows: with 10% chloral hydrate (3ml/100g)
Intraperitoneal injection of anesthesia, opens breast and exposes heart, through left ventricular cannulation, cut off right atrium, and 0.9% normal saline 200 milliliters delays
Flood irrigation is noted, and the most slowly irrigates 4% paraformaldehyde 200 milliliters, hardens with rat muscle and be preferred, at spinal cord injury being
The heart, takes and is about 4-5 centimetre of spinal cord and puts in 4% paraformaldehyde phosphate buffer fixing.Rat spinal cord after fixing is pruned
Becoming and be about 2 cm of tissue, then gradient alcohol dehydration centered by pathological changes, paraffin embedding, section, haematoxylin & eosin contaminates
Color (HE dyeing), and immunohistochemical staining, after mounting, microscope is observed.Draw again the heart of 1 month after medicine, liver,
Spleen, lung, nephridial tissue, fix with 4% paraformaldehyde.Then the serial dehydration of same standard step is carried out, paraffin embedding,
Section, HE dyes, mounting, and microscope is observed.
Figure 11-Figure 13 is rat acute spinal cord injury repairing effect evaluation.Figure 11 is each experimental group BBB scoring cartogram,
It can be seen that in addition to postoperative 1 day, the nanofibrous microsphere/hydrogel of remaining time point carrying docetaxel is combined
The BBB of system group marks apparently higher than other each group, illustrates that this medicine-carried system is conducive to acute spinal cord injury reparation.Figure 12
For the spinal cord HE coloration result of each experimental group rat different time points, in addition to sham operated rats, remaining each treatment group is in each time
Select white matter, the destruction of grey matter integrity all having in various degree, but the nanofibrous microsphere/hydrogel of carrying docetaxel is combined
System group is good compared with other treatment group at white matter, the grey matter integrity of each time point, and glial scar is significantly less than other treatment group group.
Figure 13 is the magnetic resonance photo before and after the treatment of rat half cross-section spinal cord injury model.Figure 14 is to give normal saline and carry polyenoid
The HE stained figure of 1 month each main organs after the nanofibrous microsphere of paclitaxel/hydrogel compound system.Two group ratios
Compared with it is found that after giving the nanofibrous microsphere/hydrogel compound system of carrying docetaxel each main organs of rat have no bright
Aobvious pathological changes.Nanofibrous microsphere/hydrogel compound system the vivo applications pair of the carrying docetaxel used in the present invention is described
It is nontoxic in main organs.
Medicament-carrying nano-fiber microsphere/hydrogel compound system obtained by the present invention can effectively control the slow release of medicine, and
Biodegradable macromolecular material PLA-F68-PLA and PLA-10R5-PLA can degrade in vivo voluntarily, owing to receiving
The topical of rice fiber microsphere/hydrogel compound system makes Docetaxel energy slowly sustained release, and directly damages with spinal cord
Position, traumatic part acts on, and not only significantly reduces administration number of times, also reduces toxic and side effects.
Claims (10)
1. a preparation method for medicament-carrying nano-fiber microsphere/hydrogel composites, the processing step of the method and bar
Part is as follows:
(1) by the polylactic acid-poloxamer F68-polylactic acid multi-block polymer of 46～340 parts and with polylactic acid-
The mass parts meter 8 of poloxamer F68-polylactic acid multi-block polymer～micro-pipe suppression class medicine addition of 20%
50～70 DEG C, in 2500～20000 parts of organic solvents, stirring makes it fully dissolve, and obtains settled solution A；Will be with
The stereometer 3 of solution A～the solvent B of 6 times are preheated to 50～70 DEG C in water-bath, are subsequently adding by solvent B's
Stereometer 0.1～the dispersant of 0.3%, form mixed solution C；Under agitation, mixed solvent C is slow
Join in settled solution A, continue stirring 10～30min after adding and pour in liquid nitrogen, stand 20～40min
Obtain frozen material；It is added thereto to >=the mixture of ice and water of 1 times of volume with frozen material stereometer, carries out solvent exchange
With distilled water wash 3～6 times after 24～48h, in less than 20 DEG C preservations after lyophilization, i.e. prepare the nanometer of medicine carrying
Fiber microsphere；
(2) by polylactic acid-trans poloxamer-polylactic acid multi-block polymer by concentration at least 10wt% after configuration
Amount add mix homogeneously in normal saline, then heating to 50～60 DEG C of stirrings, to form polylactic acid-trans pool Lip rivers husky
Nurse-polylactic acid multi-block polymer solution；
(3) by gained medicament-carrying nano-fiber microsphere as 5～35wt% add prepared by polylactic acid-trans pool Lip river husky
In nurse-polylactic acid multi-block polymer solution, it is uniformly mixed at 50～60 DEG C, then processes 24h in 4 DEG C
?.
The preparation method of medicament-carrying nano-fiber microsphere/hydrogel composites the most according to claim 1, the party
Polylactic acid-poloxamer F68-polylactic acid multi-block polymer used by step (1) in method, the equal molecule of its theoretical value
Amount is 1.5～3.0 × 104, and this multi-block polymer is prepared from by following methods: the method is by quality
Than the L-lactide, poloxamer F68 and total according to L-lactide and poloxamer F68 that are 0.786～2.57
The stannous octoate of quality meter 0.3% joins in reaction vessel as catalyst, under nitrogen air-flow protection, and will reaction
Thing is heated to 140-180 DEG C, stirring reaction 15-24h, is cooled to room temperature, then according to the Methods For Purification of routine.
The preparation method of medicament-carrying nano-fiber microsphere/hydrogel composites the most according to claim 1 and 2,
In the method, the organic solvent used by step (1) is in chloroform, acetone, ethanol, nitrile and oxolane
At least one；Solvent B used be glycerol, relative molecular mass be Polyethylene Glycol and the season of 200-600
At least one in penta tetrol；Micro-pipe suppression class medicine used is Docetaxel or carbadox match；Used
Dispersant is trans poloxamer 10R5 or trans poloxamer 17R4.
The preparation method of medicament-carrying nano-fiber microsphere/hydrogel composites the most according to claim 1 and 2,
In the method, the polylactic acid-trans poloxamer-polylactic acid multi-block polymer used by step (2) is according to following
Prepared by method: under inert gas shielding, by L-lactide, trans poloxamer in mass ratio 0.185～1.4
Mix with by trans poloxamer stannous octoate catalyst of 0.3% in terms of the gross mass of L-lactide, and in
130-160 DEG C of reacting by heating 5-12h, cooling, it is subsequently adding after solvent dissolves reaction gains and places into-20 DEG C
Petroleum ether precipitates, filters, be dried after repeatable operation 2～3 times, purify.
The preparation method of medicament-carrying nano-fiber microsphere/hydrogel composites the most according to claim 3, the party
In method, the polylactic acid-trans poloxamer-polylactic acid multi-block polymer used by step (2) is in accordance with the following methods
Preparation: under inert gas shielding, by L-lactide, trans poloxamer in mass ratio 0.185～1.4 with
Trans poloxamer mixes with the stannous octoate catalyst of the gross mass meter 0.3% of L-lactide, and in 130-160
DEG C reacting by heating 5-12h, cooling, it is subsequently adding after solvent dissolves reaction gains the petroleum ether placing into-20 DEG C
Middle precipitation, filters, and is dried, purifies after repeatable operation 2～3 times.
The preparation method of medicament-carrying nano-fiber microsphere/hydrogel composites the most according to claim 4, the party
Trans poloxamer 10R5 or Mn=2700 that trans poloxamer is Mn=2000 used by step (2) in method
Trans poloxamer 17R4, and the mass ratio of L-lactide and trans poloxamer 10R5 is 0.25～1.4,
L-lactide is 0.185～1.185 with the mass ratio of trans poloxamer 17R4；This polylactic acid-trans poloxamer
It is 10～50wt% that-polylactic acid multi-block polymer solution forms the critical gel strength of hydrogel, critical gel temperature
Degree is 25～35 DEG C.
The preparation method of medicament-carrying nano-fiber microsphere/hydrogel composites the most according to claim 5, should
Trans poloxamer 10R5 or Mn=2700 that trans poloxamer is Mn=2000 used by step (2) in method
Trans poloxamer 17R4, and the mass ratio of L-lactide and trans poloxamer 10R5 is 0.25～1.4,
L-lactide is 0.185～1.185 with the mass ratio of trans poloxamer 17R4；This polylactic acid-trans pool Lip river is husky
It is 10～50wt% that nurse-polylactic acid multi-block polymer solution forms the critical gel strength of hydrogel, critical gel
Temperature is 25～35 DEG C.
8. the medicament-carrying nano-fiber microsphere/hydrogel composites prepared by method described in claim 1, this is multiple
Compound is made up of colloidal sol and the medicament-carrying nano-fiber microsphere being uniformly distributed therein, medicament-carrying nano-fiber microsphere
Content is 5～35wt%, and this microsphere is the hollow microsphere constituted that naturally interweaved by nanofibers, and its particle diameter is
20～200 μm, theoretical drug loading is 8～20%, and actual drug loading is 7.45～17.32%, and envelop rate is
86.64～93.17%；In colloidal sol, the content of polylactic acid-trans poloxamer-polylactic acid multi-block polymer is at least
10wt%, its sensitive temperature >=25 DEG C.
Medicament-carrying nano-fiber microsphere/hydrogel composites the most according to claim 8, in this complex colloidal sol
The content of polylactic acid-trans poloxamer-polylactic acid multi-block polymer is 10～50wt%, and its sensitive temperature is
25～35 DEG C.
10. medicament-carrying nano-fiber microsphere/hydrogel composites described in a claim 8 is repaiied at acute spinal cord injury
Application in Fu.
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