CN106038486A - Macromolecule micelle capable of transmitting two or more antitumor drugs and preparing method thereof - Google Patents
Macromolecule micelle capable of transmitting two or more antitumor drugs and preparing method thereof Download PDFInfo
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- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The invention discloses macromolecule micelle capable of transmitting two or more antitumor drugs and a preparing method thereof. According to constitution of the macromolecule micelle, amphiphilic macromolecule or hydrophobic macromolecule material cores encapsulating the early-release antitumor drug B are wrapped by amphiphilic macromolecule material shells encapsulating the early-release antitumor drug A. The preparing method includes the steps that the amphiphilic macromolecule material and the drug released earlier are dissolved in organic solvent to form an organic solution (1), the amphiphilic macromolecule material or the hydrophobic macromolecule material for forming the micelle inner cores and the drug released later are dissolved in organic solvent to form an organic solution (2), the solution (1) and the solution (2) are connected with an annular cavity and an inner cavity for forming micelle droplets of a dropwise adding device respectively and are added into a water phase through the dropwise adding device to form shell-core nano particle droplets, and the multi-drug macromolecule micelle is obtained after the organic solvent is removed. Chemical reaction caused by incompatibility among the drugs is avoided, and the drugs are sequentially released according to clinical needs.
Description
Technical field
The present invention relates to transmit antitumor drug technology, more specifically, relate to one can transmit simultaneously two kinds or
Macromolecule micelle of two or more antitumor drug and preparation method thereof, belongs to pharmaceutical preparations technology field.
Background technology
Chemotherapy is the common method for the treatment of cancer, has direct inhibitory action to tumor, and clinical practice ratio is wide.But by
In complexity and the heterogeneity of tumor, usually make oncotherapy that the drug resistance to medicine occurs, cause chemotherapy of tumors failure.Will
There is the therapeutic strategy combinational drug therapy that the multi-medicament of the different mechanism of action is administered simultaneously, shown in medical practice
Illustrate and treat more preferable effect than single medicine, thus only the most gradually lose meaning by single little molecule naked medicine treatment cancer.
Macromolecule micelle narrow size distribution, the core-shell structure of its uniqueness, hydrophobic core is wrapped up by the most hydrophilic shell
The characteristic come is during beneficially macromolecule micelle resides in blood of human body.When macromolecule micelle is as pharmaceutical carrier, have high
Drug loading, macromolecular chain couples functional group can obtain the characteristic of target tumor tissue or tumor cell.Macromolecule micelle typical case
Distribution of sizes from tens nanometers to hundreds of nanometer, not only make it escape kidney and filter, and compare microgranule, liposome and nanometer
Ball, such distribution of sizes allows them more can remain into [Progress of drug-loaded in tumor tissues
polymeric micelles into clinical studies,J.Control.Release 2014,190,465-476】。
Therefore, macromolecule micelle be capable of medicine collaborative, select and safe medication, be the most promising drug nanosystems it
One [Polymeric Micelles for Multi-Drug Delivery in Cancer AAPS PharmSciTech,
2015,16(1),10-20】。
Macromolecule micelle is open for the existing Patents of medicine carrying.The patent documentation of Publication No. CN201210542153.X
Disclose bag simultaneously carry hydrophobic antitumor drug and the polymer nano micelle compositions of multidrug-resistance reversal agent pluronic and
Its preparation method.The patent documentation of Publication No. CN201310039396.6 discloses and uses special block copolymer, makes suitable
Platinum is combined by coordination with block copolymer, and amycin and block copolymer are compounded to form micelle by electrostatic interaction, from
And reach to transmit the purpose of two kinds of antitumor drug simultaneously.The patent documentation of Publication No. CN201510226344.9 discloses profit
Occur be coordinated and transmit amycin simultaneously with carboxyl in multi-arm copolymer polyglutamic acid block or aspartic acid block and cisplatin.?
These patents are formed a section in the material of macromolecule micelle or material can with the medicine generation electrostatic interaction of load to be wrapped or
Coordination.The patent documentation that inventor is retrieved, not by the special role of macromolecule glue beam material with medicine, i.e. uses
The common amphiphilic macromolecule preparing carrier micelle such as polyethylene glycol ester, reach to be simultaneously load into two kinds or two kinds with
The patent of upper medicine there is not yet.But paper report also begins to relate to the content of this respect, such as PEG-PCL micelle
It is higher by 3.3 than the picked-up of the cell in vitro of the mixture of naked medicine and single medicine micelle and cytotoxicity that bag carries curcumin and Lei Bai mycin
[Mohanty A, Mohanta G, Micelle-assisted combination therapies for effective again
Glioblastoma treatment:an in-vitro assessment, Anti-Cancer Drugs 2015,26 (3),
312-322.】；Being carried paclitaxel, cyclopamine and the PEG-PCL micelle of gossypol by peritoneal injection bag, ratio is individually
Bag carries the PEG-PCL micelle of paclitaxel tumor inhibitory effect when Ovarian Cancer Model is treated and to get well, survival
Higher [Shin H, Alani A, Rao D, Rockich N, Kwon G, the Multi-drug loaded polymeric of rate
micelles for simultaneous delivery of poorly soluble anticancer drugs,Journal
of Controlled Release 2009,140,294-300.】.But carefully analyze these researchs it is found that these medicines are
It is downloaded in micelle by bag simultaneously, discharges from micelle the most simultaneously, it is impossible to by needing order release clinically；More important
Be a little to cannot be avoided chemical reaction that is incompatible between medicine and that cause, such as problems such as precipitation, toxicity superpositions.
Summary of the invention
For deficiency and the present situation of existing transmission antitumor drug technology, the purpose of the present invention aims to provide a kind of transmittable
Macromolecule micelle of two or more antitumor drug and preparation method thereof, to realize by needing order release clinically,
Avoid the incompatible adverse chemical reaction caused between medicine, improve the effect of multiple medicines combined therapy tumor.
The basic thought of the present invention is to use the micelle preparation method improved to build multiple medicines macromolecule micelle, forms macromolecule
In the material of micelle, at least one is that the amphipathy macromolecule having and forming micelle ability (not only has hydrophilic segment but also have in molecule
There is oleophilic moiety)；Multiple insoluble drug is wrapped the most respectively inner nuclear material and the cladding material being downloaded to macromolecular material micelle
In, form multiple medicines macromolecule micelle, it is to avoid the incompatible and chemical reaction that causes between medicine, and by needing order to release clinically
Medicine.
The present invention provides the macromolecule micelle of two or more antitumor drug transmittable, for nucleocapsid structure, its bag
The amphiphilic macromolecule material shell being loaded with formerly release antitumor drug A is wrapped in and is loaded with at the two of rear release antitumor drug B
Parent's macromolecule or hydrophobic polymer material core.
In the technical scheme of above-mentioned macromolecule micelle, the described antitumor drug A formerly discharged can be a kind of antitumor
Medicine, it is possible to for two or more antitumor drug, when for two or more antitumor drug, medicine it
Between should be compatible；In like manner, the described antitumor drug B in rear release can be a kind of antitumor drug, it is possible to be two kinds or two
Kind above antitumor drug, when for two or more antitumor drug, should be compatible between medicine.
In the technical scheme of above-mentioned macromolecule micelle, the hydrophobic block of described amphiphilic macromolecule material and hydrophobicity high score
The preferred degradable polyester of sub-material, Merlon or methylcellulose, ethyl cellulose；Further preferably in degradable polyester
Polylactic acid, poly-lactone or their copolymer or the copolymer of polyester and Merlon.
In the technical scheme of above-mentioned macromolecule micelle, in described hydrophobic polymer material or amphiphilic macromolecule material
Hydrophobic block preferred molecular weight is 1000～10000 daltonian macromolecular materials；The described preferred molecule of amphiphilic macromolecule material
Amount is 2000～30000 daltonian macromolecular materials.
Above-mentioned two or more antitumor drug macromolecule micelle transmittable can be by comprising the following steps that
Prepared by method:
(1) amphiphilic macromolecule material is dissolved in organic solvent formation macromolecular material organic solution 1, by hydrophobicity or
Amphipathy macromolecule material is dissolved in organic solvent formation macromolecular material organic solution 2, adds formerly in organic solution 1
The medicine A of release, the medicine B of release after being added in organic solution 2；The macromolecular material weight concentration of organic solution is
0.01～20%, preferably 0.1～10%.；Medication amount is macromolecular material weight 0.1～30% added in organic solution,
Preferably 1～20%；
(2) will be placed in and the coaxial Dropping feeder being used for being formed micelle drop containing the organic solution 1 of formerly release medicine A
In the container that outer annular chamber is connected, will be placed in containing the organic solution 2 at rear release medicine B and be used for forming micelle drop
In the container that coaxial Dropping feeder inner chamber is connected, control coaxial Dropping feeder outer annular chamber with the solution in inner chamber with 50-
The 1000 identical speed of μ L/min, are under agitation added drop-wise in aqueous phase, form shell core nanoparticle drop；
(3) the core-shell structure micelle drop that dropping is formed, after removing organic solvent by volatilization or dialysis, i.e. obtains passing
Give two or more antitumor drug macromolecule micelle.
In the technical scheme of above-mentioned preparation method, the consumption of described aqueous phase is in described organic solution 1 and organic solution 2
5-100 times of organic solvent phase gross weight, i.e. the micelle drop of core-shell structure is added dropwise in substantial amounts of water.
In the technical scheme of above-mentioned preparation method, when the macromolecular material forming kernel portion is also amphiphilic macromolecule material
During material, form the amphiphilic macromolecule material of shell part and form the amphiphilic macromolecule material of kernel portion, can be same two
Parent's macromolecular material, it is also possible to be different two kind amphiphilic macromolecule materials.
Using the macromolecule micelle that can transmit two or more antitumor drug prepared by the inventive method, shell is
Can form the amphipathy macromolecule material of macromolecule micelle, bag is loaded with the antitumor drug formerly discharged by clinical release order,
Kernel is amphipathy macromolecule material or the hydrophobic polymer material that can form macromolecule micelle, and bag is loaded with by clinical release suitable
Sequence is at the antitumor drug of rear release, it is ensured that two or more antitumor drug of macromolecule micelle package-contained is pressed completely
Need order release clinically, improve the effect of multiple medicines combined therapy tumor, overcome the medicine-carrying polymer glue of prior art
Bundle, the various medicines that bag is downloaded in micelle are to be mingled in macromolecule micelle, and various medicines discharge from micelle the most simultaneously,
Can not be by needing order release clinically, it is impossible to avoid chemical reaction that is incompatible between medicine and that cause, such as precipitation, toxicity superposition
Etc. problem.The macromolecule micelle of two or more antitumor drug transmittable that the present invention provides, can be completely by clinically
Needs order release, can be used for injecting release treatment.Until the present invention completes, inventor is at patent documentation or other document
In yet there are no the relevant report about present invention.
The present invention, relative to prior art, sums up and has the most prominent following advantage and technique effect:
(1) macromolecule micelle that the present invention provides, two or more incompatible antitumor drug is suitable by release
Sequence bag the most respectively is loaded in shell and the kernel of macromolecule micelle, has reached two or more incompatible antineoplastic agent
Thing wraps simultaneously and is downloaded in macromolecule micelle, it is possible to achieve multiple medicines combination carries out release according to being actually needed release order, improves
Multiple medicines combined therapy effect.
(2) method of the macromolecule micelle of preparation two or more antitumor drug transmittable that the present invention provides,
Being a kind of brand-new method, the method technique of the present invention is simple, except the macromolecular material of Bao Zaiyong, a small amount of organic solvent and
Outside water, it is not necessary to other additive.
Accompanying drawing explanation
Fig. 1 is to prepare the Dropping feeder structural representation containing two or more antitumor drug macromolecule micelle.
Fig. 2 is by two kinds of amphiphilic macromolecule mPEG-PCL and amphiphilic macromolecule mPEG-PCL-PDEA (having pH sensitivity)
Form double macromolecular material micelle and the acid-base titration curve (embodiment 1) of mixing macromolecule micelle.
Fig. 3-1 be kernel be hydrophobic polymeric material, shell be the height that the bag that amphiphilic macromolecule is constituted is loaded with two kinds of medicines
The structural representation of molecule micelle.
Fig. 3-2 is the high score that the bag that respectively two kinds different amphiphilic macromolecules of kernel and shell are constituted is loaded with two kinds of medicines
The structural representation of sub-micelle.
In Fig. 3-1 and Fig. 3-2, round dot represents a kind of medicine or drug regimen, and rectangular dots represents another kind of medicine or medicine
Thing combines.
Fig. 4-1 be the kernel that the present invention provides be hydrophobic polymer material, shell be amphiphilic macromolecule material constitute
The transmission electron microscope picture of micelle.
Fig. 4-2 is the transmission electricity of the mixed micelle of hydrophobic polymer of the prior art and the formation of a kind of amphiphilic macromolecule
Mirror figure.
Fig. 5 is that the medicine DOX that the present invention provides constitutes core and medicine DOX and amphiphilic macromolecule with hydrophobic polymer material
Material constitutes the contrast (embodiment 5) of two kinds of double macromolecule micelle drug release patterns of shell.
Detailed description of the invention
Below by embodiment, the present invention is specifically described.Be necessary it is pointed out here that be that following example are served only for
The invention will be further described, it is impossible to is interpreted as limiting the scope of the invention, professional and technical personnel in the field's root
Some nonessential improvement and the adjustment made according to the content of the invention described above, still fall within protection scope of the present invention.
In each embodiment below, involved component percentages, number, unless otherwise indicated, it is weight percent
Number, parts by weight.
Embodiment 1
Constitute the material selection amphiphilic macromolecule material poly glycol monomethyl ether-polycaprolactone of multiple medicines macromolecule micelle
And poly glycol monomethyl ether-polycaprolactone-polymethylacrylic acid lignocaine ethyl ester (mPEG-PCL-PDEA) (mPEG-PCL).
The molecular weight of mPEG-PCL is 3000, and the molecular weight of hydrophobic block PCL is 2000；The molecular weight of mPEG-PCL-PDEA is 5500,
Wherein PCL-PDEA is collectively as hydrophobic block, and molecular weight is 3500, and PDEA has pH sensitivity；Amphiphilic macromolecule is molten
Solution forms the organic solution 1 and 2 of 1% in oxolane, by organic solution 1 and 2 respectively with exocoel phase in coaxial Dropping feeder
Even, control coaxial rate of addition 100 μ L/min, be under agitation added drop-wise in 5 times of aqueous phases, form shell core micelle drop, remove completely
Macromolecule micelle is obtained after removing organic solvent.
B-O micelle be mPEG-PCL at internal layer, mPEG-PCL-PDEA is at outer layer；B-I micelle be mPEG-PCL at outer layer,
MPEG-PCL-PDEA is at internal layer；M micelle is that both are mixed to form micelle, it appeared that M micelle and B-O micelle are at pH 5.0-
Have an obvious buffer platform between 7.0, and pure water and B-I micelle do not occur in this region not similar result (see
Fig. 2 amphiphilic macromolecule mPEG-PCL and pH sensitivity amphiphilic macromolecule mPEG-PCL-PDEA formed double macromolecular material micelle and
The acid-base titration curve of mixing macromolecule micelle).This is because the outer layer of M micelle and B-O micelle has PDEA segment, its end
Tertiary amine group has the phenomenon of protonation, so there will be the platform of buffering；On the contrary, the outer layer at pure water and B-I micelle does not has
PDEA segment.Meanwhile, although it appeared that pure water and B-I micelle the most do not occur buffer platform between pH5.0-7.0,
But B-I micelle pH starts the position of change than pure water more rearward, and this is possibly due to when mPEG-PCL-PDEA is in micelle internal layer
Time, OH-is diffused into inside micelle, and it is inside micelle that deprotonation occurs, and the pH value being measured to remains most micelle
Solution, thus, neither occur quick pH value to change, also buffer platform occurs the most faster；And when PDEA is inside micelle
Deprotonation complete after, solution directly embodies pH value hop.Therefore, two kinds of amphiphilic macromolecules can also form Fig. 3 (II)
Shown micellar structure, thus in bag load multi-medicament the most respectively to macromolecular material micelle.
Table 1 is the particle diameter of the mixed micelle M of double macromolecular material micelles of recording of this embodiment and contrast and particle diameter divides
Cloth and z current potential.
Table 1
Embodiment 2
The material selection amphiphilic macromolecule constituting multiple medicines macromolecule micelle is polycaprolactone-ss-poly-phosphatidyl choline (PCL-
Ss-PMPC, middle-ss-is disulfide bond, is the amphiphilic macromolecule with reduction-sensitive), molecular weight is 5000；Polylactic acid
(PLA), molecular weight is 2,000；PCL-ss-PMPC and PLA is dissolved separately in the mixed of oxolane and methanol (volume ratio 2:1)
Forming concentration in bonding solvent is 0.1% organic solution 1 and 0.05% organic solution 2, organic solution 1 and 2 is dripped with coaxial respectively
In feeder apparatus, exocoel is connected, and controls coaxial rate of addition 500 μ L/min, is under agitation added drop-wise in 50 times of aqueous phases, forms shell core
Micelle drop, obtains double high molecular micelle after completely removing organic solvent.Micelle particle diameter is 185 ± 3.9, and z current potential is-22.7
±1.2。
Transmission electron microscope such as Fig. 4-1 of this double high molecular micelle, illustrates hydrophobicity in the macromolecule micelle of the present invention
Macromolecule is completely in the inside of micelle, is wrapped up by amphiphilic macromolecule, is totally different from the hydrophobic polymer of prior art
With the structure (Fig. 4-2) that a kind of amphiphilic macromolecule forms mixed micelle.Therefore, illustrate the macromolecule micelle that the present invention provides,
The multi-medicament of slightly solubility can be wrapped the most respectively in the inner layer material and the cladding material that are downloaded to macromolecular material micelle, as
Fig. 4-1, forms multiple medicines macromolecule micelle.
Embodiment 3
The layer materials constituting multiple medicines macromolecule micelle all selects PEG-PCL, and wherein hydrophilic block is gathered
Molecular weight 5000 dalton of ethylene glycol, hydrophobic block polycaprolactone 20000 dalton；By 1 part of methotrexate and 10 parts of high scores
Son is dissolved in pyrroles and forms 5% solution 1, and 2 parts of 5-fluorouracil and 5 parts of macromolecule dissolutions are formed in oxolane 2%
Solution 2；Solution 1 is placed in the container being connected with coaxial syringe needle outer layer, solution 2 is placed in the appearance being connected with coaxial syringe needle internal layer
In device, control ectonexine solution injection rate and be under agitation slowly dropped in the aqueous phase of 10 times；After being added dropwise to complete micelle is molten
Liquid is put into put in the bag filter that molecular cut off is 3000 in distilled water and is dialysed until organic solvent completely removes.The load obtained
Medicine micelle particle diameter is 97 ± 13nm, the envelop rate 82.5 ± 7.2% of 5-fluorouracil, the envelop rate of methotrexate 84.8 ±
9.3%.
Embodiment 4
Constitute the material selection amphiphilic macromolecule material poly glycol monomethyl ether-polycaprolactone of multiple medicines macromolecule micelle outer layer
(mPEG-PCL), wherein the molecular weight of poly glycol monomethyl ether is 2000, and the molecular weight of polycaprolactone is 5000；Inner layer material selects
With polylactic acid (PLA), wherein the molecular weight of polylactic acid is 10000 dalton；By 0.5 part of camptothecine, 2.5 parts of curcumins and 10 parts
MPEG-PCL is dissolved in oxolane and forms 10% solution 1, and 1.5 parts of 5-fluorouracil and 5 parts of PLA are dissolved in dichloromethane
Middle formation 0.5% solution 2；Solution 1 is placed in the container being connected with coaxial syringe needle outer layer, solution 2 is placed in and coaxial syringe needle
In the container that internal layer is connected, control ectonexine solution injection rate and be under agitation slowly dropped in the aqueous phase of 7 times；It is added dropwise to complete
After vapor away organic solvent completely, the carrier micelle particle diameter obtained is 215 ± 12nm, carry Ah's camptothecine 3.1 ± 2.7%, encapsulating
Rate 75.5 ± 2.2%；Curcumin drug loading 8.4 ± 4.3, envelop rate 82.6 ± 3.1%；5-fluorouracil 2.8 ± 2.4%, bag
Envelope rate 63.5 ± 7.2%.
Embodiment 5
Material is same with embodiment 2, weighs a certain amount of amycin and is dissolved in oxolane and methanol (body together with polymer
Long-pending than 2:1) mixed solvent in form the organic solution of concentration 1%, by organic solution 1 and 2 respectively with in coaxial Dropping feeder
Exocoel is connected, and controls coaxial rate of addition 100 μ L/min, is under agitation added drop-wise in 10 times of aqueous phases, forms shell core micelle drop,
Double high molecular micelle is obtained after completely removing organic solvent.Only in kernel PLA bag carry amycin micelle be SDI, i.e. Ah
Mycin is only dissolved into the double macromolecule micelles obtained in the organic solution of PLA；Only in shell PCL-ss-PMPC, bag carries amycin
(DOX) carrier micelle is that SDO, i.e. amycin are only dissolved into the double macromolecule glues obtained in the organic solution of PCL-ss-PMPC
Bundle；The drug release patterns of the carrier micelle obtained such as accompanying drawing 5, it can be seen that no matter be the ring at the pH 7.4 simulating blood
Border is still in reducing environment, and when being all in shell material than medicine when medicine DOX is in nuclear material, rate of release is slow,
Therefore, during release result demonstrates the core of double macromolecule micelle and shell, medicine carrying has Cheng Shunxu releasing properties.
Embodiment 6
Polycaprolactone selected by the internal layer macromolecular material constituting multiple medicines high molecular nanometer grain, and molecular weight is about 6000 dongle
, polycaprolactone-polyethylene glycol selected by outer layer macromolecular material, and wherein the molecular weight of polycaprolactone block is about 15000 dongle
, the molecular weight of Polyethylene Glycol block is about 10000 dalton.3 parts of curcumins and 10 parts of polycaprolactone-polyethylene glycols are dissolved
In 100 parts of oxolanes, form 0.5% solution 1,1 part of amycin and 10 parts of polycaprolactones are dissolved in 100 parts of oxolanes
Middle formation 2% solution 2；Solution 1 is placed in the container being connected with coaxial Dropping feeder outer layer, solution 2 is placed in and coaxial needles
In the container that head internal layer is connected, control ectonexine solution injection rate 150 μ L/min and be under agitation slowly dropped to the water of 20 times
Xiang Zhong, continues stirring until organic solvent completely removes after being added dropwise to complete.The carrier micelle particle diameter obtained is 179 ± 23nm, carries
Amycin amount 4.5 ± 0.9%, envelop rate 88.6 ± 4.7%；Curcumin drug loading 8.7 ± 1.2, envelop rate 92.5 ± 3.3%.
Claims (10)
1. can transmit the macromolecule micelle of two or more antitumor drug, for nucleocapsid structure, it is characterised in that bag is loaded with
Formerly the amphiphilic macromolecule material shell of release antitumor drug A is wrapped in and is loaded with the amphiphilic height at rear release antitumor drug B
Molecule or hydrophobic polymer material core.
The macromolecule micelle of two or more antitumor drug transmittable the most according to claim 1, its feature exists
In, the described antitumor drug A formerly discharged is one or more compatible antitumor drug, described resisting in rear release
Tumour medicine B is the antitumor drug that one or more are compatible.
The macromolecule micelle of two or more antitumor drug transmittable the most according to claim 1 and 2, its feature
Be, the hydrophobic block of described amphiphilic macromolecule material and hydrophobic polymer material be degradable polyester, Merlon or
Methylcellulose, ethyl cellulose.
The macromolecule micelle of two or more antitumor drug transmittable the most according to claim 3, its feature exists
In, the hydrophobic block of described amphiphilic macromolecule material and hydrophobic polymer material are the polylactic acid in degradable polyester, have gathered
The copolymer of lactone or their copolymer or polyester and Merlon.
The macromolecule micelle of two or more antitumor drug transmittable the most according to claim 4, its feature exists
In, the hydrophobic block of amphiphilic macromolecule material and the molecular weight of hydrophobic polymer material are 1000～20000 dalton.
The macromolecule micelle of two or more antitumor drug transmittable the most according to claim 4, its feature exists
In, the molecular weight of amphiphilic macromolecule material is 2000～30000 dalton.
7. the method for described two or more antitumor drug macromolecule micelle transmittable of one of preparation claim 1 to 6,
It is characterized in that, mainly comprise the following steps that:
(1) amphiphilic macromolecule material is dissolved in organic solvent formation macromolecular material organic solution 1, by hydrophobicity or amphiphilic
Property macromolecular material be dissolved in organic solvent formation macromolecular material organic solution 2, add in organic solution 1 and formerly discharge
Medicine A, after being added in organic solution 2 release medicine B；The macromolecular material weight concentration of organic solution be 0.01～
20%, medication amount is macromolecular material weight 0.1～30% added in organic solution；
(2) will be placed in and the coaxial Dropping feeder outer layer being used for being formed micelle drop containing the organic solution 1 of formerly release medicine A
In the container that annular chamber is connected, will be placed in containing the organic solution 2 at rear release medicine B and be used for forming the coaxial of micelle drop
In the container that Dropping feeder inner chamber is connected, control coaxial Dropping feeder outer annular chamber with the solution in inner chamber with 50-1000 μ L/
The identical speed of min, is under agitation added drop-wise in aqueous phase, forms core-shell structure micelle drop；
(3) the core-shell structure micelle drop that dropping is formed, after removing organic solvent by volatilization or dialysis, i.e. obtains transmittable two
Plant or two or more antitumor drug macromolecule micelle.
The preparation method of two or more antitumor drug macromolecule micelle transmittable the most according to claim 7,
It is characterized in that, the consumption of described aqueous phase is the 5-of the organic solvent phase gross weight in described organic solution 1 and organic solution 2
100 times.
9. according to the preparation side of two or more antitumor drug macromolecule micelle transmittable described in claim 7 or 8
Method, it is characterised in that the macromolecular material weight concentration in organic solution is 0.1～10%.
10. according to the preparation side of two or more antitumor drug macromolecule micelle transmittable described in claim 7 or 8
Method, it is characterised in that the medication amount added in organic solution is the 1～20% of macromolecular material weight.
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