CN109464402A - A kind of multifunctional nano pharmaceutical composition and preparation method thereof - Google Patents
A kind of multifunctional nano pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN109464402A CN109464402A CN201811360486.4A CN201811360486A CN109464402A CN 109464402 A CN109464402 A CN 109464402A CN 201811360486 A CN201811360486 A CN 201811360486A CN 109464402 A CN109464402 A CN 109464402A
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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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to nano biological field of medicaments, and in particular to a kind of multifunctional nano pharmaceutical composition and preparation method thereof.Described pharmaceutical composition includes the active constituent of carrier and load on the carrier, and the carrier is HPMA-NAS-PLA polymer, and the active constituent is hydrophobic drug；The carrier is obtained by the poly- N-2- hydroxypropyhnethacrylamide HMPA of acrylic acid N-hydroxy-succinamide ester NAS connection and polylactic acid PLA.Multifunctional nano pharmaceutical composition provided by the invention, can carry hydrophobe drug, especially high to hydrophobic medicine drugloading rate.It is prepared by nanoprecipitation method, obtained pharmaceutical composition is having a size of nanoscale, and narrowly distributing.In addition, the n-hydroxysuccinimide group contained on support copolymer, can be covalently attached with the material containing amino, there are the potentiality for carrying genomic medicine.Therefore there is good chemotherapy and gene therapy to be combined prospect.
Description
Technical field
The invention belongs to nano biological field of medicaments, and in particular to a kind of multifunctional nano pharmaceutical composition and its preparation side
Method.
Background technique
Nanometer medicine-carried system be using the nanoparticle of partial size between 1-1000nm as carrier, it is (close and distant to variety classes
Water) drug realization conveys jointly and sustained-release and controlled release.The characteristic that nano medicament carrying system has due to itself such as improves conventional medicament
Solubility, pharmacokinetics and in terms of deficiency, realize drug be passively or actively targeting transport and it is various
Drug release is triggered under sensitive condition, to greatly enhance therapeutic effect.Thus have broad application prospects.Nano drug-carrying system
System can use itself special structure and performance characteristic, overcome the problems, such as many insoluble in classic chemotherapy drug.
Nano medicament carrying system is compared with other drugs carrier, and have the advantage that (1) overcomes multidrug resistance: partial size is big
Enter cell in the endocytic pathway that the particle of 500nm mainly passes through dependence energy；Particle of the partial size between 200-500nm is main
It is to rely on the endocytosis that caveolae (alveole, small recessed etc.) is mediated and enter cell；Nanometer of the partial size between 100-200nm
The phagocytosis that particle relies primarily on clathrin (clathrin) mediation enters cell.This mode of entrance can overcome cell
Membrane surface proteins (such as P- glycoprotein), which pump, acts on the outlet of drug intracellular, reduces the MDR effect of tumour cell；(2) medicine is improved
Object targeting: when chemotherapeutics is distributed in normal tissue, toxic side effect can be generated to tissue, limits dosage；But it is administered
Dosage is few to make tumor tissues drug concentration too low again, and expected therapeutic effect is not achieved.Nano-carrier system large specific surface area,
Functional group is more, and surface modification is carried out to it or modifies the targeting that can be improved to tumor tissues or cell, efficiently by drug
It is transported to and needs to treat lesions position；(3) improve biocompatibility: after drug enters body by blood circulation, it is a part of because
It is excreted for extravasation or kidney scavenging effect, drug concentration reduces, and therapeutic effect weakens；To reach therapeutic purposes, usually need
It improves dosage or the mode of continuous drip is taken to be administered, substantially increase treatment cost.And nano medicament carrying system can lead to
It overregulates carrier physicochemical characteristics (such as material structure, particle size, charge density), removing of the reduction body to drug as far as possible
Effect extends stabilization time of the drug in the circulatory system, improves drug effect；(4) dewatering medicament solubility: some drugs is improved
(such as taxol, curcumin) contains a large amount of lipophilic groups, and solubility is low in water, is difficult to prepare suitable form of administration.With
Amphipathic nature material polyethylene glycol polylactic acid (PEG-PLA) block copolymer is the nanoparticle that carrier is prepared, and can provide parent
Water environment, and hydrophobic environment can be provided, in conjunction with drug molecule after can greatly enhance dewatering medicament in water
Solubility and vivo medicine concentration significantly enhance the therapeutic effect of chemotherapeutics.
Summary of the invention
In view of the drawbacks of the prior art, the present invention provides a kind of multifunctional nano pharmaceutical compositions and preparation method thereof.
Realize that the object of the invention technical solution is as follows:
A kind of multifunctional nano pharmaceutical composition, the active constituent including carrier and load on the carrier, wherein institute
Stating carrier is HPMA-NAS-PLA polymer, and active constituent is hydrophobic drug；The work of the carrier and load on this carrier
Property ingredient formed nano particle；
Wherein the carrier is by the poly- N-2- hydroxypropyhnethacrylamide of acrylic acid N-hydroxy-succinamide ester NAS connection
HMPA and polylactic acid PLA obtain.
Preferably, the nanoparticle size is 50-1000nm；Preferably, the nanoparticle size is 50-300nm.
In Nano medication composition of the present invention, the mass ratio of the carrier and the hydrophobic drug is (20-
150):1；Preferably (30-60): 1；Optimum quality ratio is 50:1.
Nano medication composition of the present invention, the hydrophobic drug are taxol.
About the carrier: specifically, the poly- HPMA-NAS-PLA amphipathic nature block polymer is by acrylic acid N- hydroxyl
The poly- N-2- hydroxypropyhnethacrylamide HMPA of base succinimide ester NAS connection and polylactic acid PLA obtain.
Specifically, in the polymer architecture: being connected between NAS and HPMA with carbon-carbon double bond, PLA is grafted using its-OH
Copolymerization is on HPMA.
Wherein, in the HPMA-NAS-PLA polymer, mole of N-2- hydroxypropyhnethacrylamide and lactide
Than for (4-8): (1-2)；
Preferably, the ratio of m and n is (4-5): 1；More preferable 4:1.Under aforementioned proportion, obtained product stability
It is best with yield, significantly it is better than other ratios.
Polymer of the present invention, weight average molecular weight 8000-10000Da, such polymer have good dissolution
Property and stability.
Preferably, in the polymer, the poly- N-2- hydroxypropyl first of the acrylic acid N-hydroxy-succinamide ester connection
The mass ratio of base acryloyl (HPMA-NAS) and lactide (LA) are 1:(20-80).
Preferably, carrier of the present invention is prepared by following methods: by N-2- hydroxypropyhnethacrylamide and
HPMA-NAS polymer is obtained after the polymerization of acrylic acid N-hydroxy-succinamide ester, then by LA (lactide) and the HPMA-NAS
Polymer polymerizing obtains HPMA-NAS-PLA polymer.
Preferably, with molar ratio computing, the N-2- hydroxypropyhnethacrylamide and acrylic acid n-hydroxysuccinimide
The molar ratio of ester NAS is (16-32): 1；And/or the molar ratio of the lactide and the HPMA-NAS polymer is (4-8):
1。
Or, by quality ratio, the N-2- hydroxypropyhnethacrylamide and acrylic acid N-hydroxy-succinamide ester NAS
Mass ratio be (260-300): (4-5)；And/or the mass ratio of the lactide and HPMA-NAS polymer is (50-70):
1；It is highly preferred that the mass ratio of the lactide and the HPMA-NAS polymer is 60:1.
In system, suitable concentration ratio between reactant need to be kept, facilitates the generation and positive progress of reaction.As
It is highly preferred that the concentration of the N-2- hydroxypropyhnethacrylamide in the reaction system is 0.1-0.2g/mL；The lactide
Concentration in the reaction system is 1-2g/mL.
Specifically, include the following steps:
(1) N-2- hydroxypropyhnethacrylamide and NAS carry out polymerization reaction under chain initiator effect, and precipitating obtains
HPMA-NAS polymer；
(2) under organic amine effect, HPMA-NAS polymer is aggregated reacts to obtain HPMA-NAS- for LA and step (1) gained
PLA polymer.
In step (1):
The chain initiator is preferably chosen from one in azo-bis-iso-dimethyl AIBME, azodiisobutyronitrile AIBN
Kind, more preferable azo-bis-iso-dimethyl.Select azo-bis-iso-dimethyl as chain initiator can efficient initiation reaction,
And nonhazardous, industrial production preferably.
It is highly preferred that the dosage of the chain initiator is 5-10mM.
The precipitating is carried out with precipitating reagent, the precipitating reagent is alcohol-ether mixture；The preferably mixture of methanol and ether
(preferably methanol/ether=1/8).Inventor once attempted a variety of different conventional precipitating reagents, did not obtained good technology effect
Fruit (the use of the product state that mixture of ice and water precipitates being such as oily liquids, be unable to meet production demand)；By largely grinding
The outstanding technical effect for being surprised to find that can there is except being expected when precipitating reagent is alcohol-ether mixture is studied carefully, especially when methanol/second
When ether=1/8, effect is especially prominent.
The reaction temperature of the polymerization reaction is 50-60 DEG C, and the reaction time is 20-25 hours.
In step (2): the organic amine is preferably triethylamine.
Preferably, the mass volume ratio of the HPMA-NAS polymer and the organic amine is (0.2-1) g/1mL；It is more excellent
Select (0.2-0.5) g/1mL.
It in this step, is precipitated with precipitating reagent, the water three times that the precipitating reagent is 0 DEG C.Using 0 DEG C of water three times as heavy
Shallow lake agent can make the reaction product of high temperature (95 DEG C) reach instantaneous temperature reduction degree, and not introduce new impurity, obtained reaction product
Purity is improved.
In this step, the reaction temperature of the reaction is 90-98 DEG C (preferably 95 DEG C), the reaction time 12 hours；It is preferred that anti-
At once it carries out under nitrogen protection.
Preparation method of the present invention, step (a) carries out in the system of organic solvent with step (b), described to have
Solvent is preferably all anhydrous dimethyl sulphoxide.Make solvent with anhydrous dimethyl sulphoxide, ensure that the chemical reaction can be tight
It is carried out under the conditions of lattice are anhydrous；Dissolubility is higher, reacts more thorough；Boiling point is high, stability is good.And for reaction temperature etc. its
His reaction condition, which can more be conducive to the positive of reaction, to carry out.
It will be understood by those skilled in the art that may also include the product for obtaining precipitating with three times during made above
Washing repeatedly (as three times), after the completion of washing, puts it into the step of drying in vacuum oven.
A kind of multifunctional nano pharmaceutical composition, the active constituent including carrier and load on this carrier, wherein described
Carrier is that the poly- N-2- hydroxypropyhnethacrylamide of acrylic acid N-hydroxy-succinamide ester connection and polylactic acid block are total to
Polymers；Active constituent is hydrophobic drug taxol, and the active constituent of the carrier and load on this carrier forms nanometer
Grain.Preferably, the nanoparticle size is 50-1000nm.It is further preferred that the nanoparticle size is 50-
300nm。
The present invention further provides the preparation method of Nano medication composition described in above-mentioned any one technical solution, packets
Include following steps:
The HPMA-NAS-PLA polymer is dissolved with the hydrophobic drug and is uniformly mixed to obtain mixed solution, to
The mixed solution is added dropwise in water three times, after dialysis freeze-drying to obtain the final product.
Specifically, using following steps:
(a) the HPMA-NAS-PLA polymer is dissolved in organic solvent unmixing with water, obtains carrier solution；
(b) hydrophobic drug is dissolved in organic solvent unmixing with water, obtains the drug solution；
(c) carrier solution is slowly added dropwise in the drug solution；
(d) above-mentioned carrier solution and hydrophobic drug solution are added dropwise in Xiang Sanci water and obtains mixed solution；
(e) it dialyses to the mixed solution and is washed after removing organic solvent, is lyophilized to obtain the final product.
In preparation method of the present invention, step (a), in the carrier solution, the HPMA-NAS-PLA polymerization
The concentration of object is 15-25mg/mL, preferably 20mg/mL.
Step (b), in the drug solution, the concentration of the hydrophobic drug is 1-3mg/ml；
The carrier solution is slowly added dropwise in the drug solution by step (c)；Grain can be formed by being slowly added dropwise dropwise
The optimal nano particle of diameter homogeneity.Increase rate of addition or continuous be added dropwise easilys lead to nano particle coagulation, influences institute
Obtained nano particle molding.
Step (d) further includes the process of magnetic agitation 20-40min after obtaining mixed solution；
Step (e), for the bag filter molecular weight used of dialysing for 3000-3500Da, the time of dialysis is 65-75h.
In preparation method of the present invention, the speed " being added dropwise " described in step (d) can be according to art technology
The common sense of personnel operates, compare herein Preferable scheme is that: be about the rate according to 100uL/min.
Multifunctional nano pharmaceutical composition provided by the invention, can carry hydrophobe drug, especially carry to hydrophobic medicine
Dose is high.The pharmaceutical composition is prepared by nanoprecipitation method, and obtained pharmaceutical composition is having a size of nanoscale, and narrowly distributing.This
Outside, the n-hydroxysuccinimide group contained on support copolymer, can be with material (such as nucleoprotamine, poly- second containing amino
Alkene imines etc.) it is covalently attached, there are the potentiality for carrying genomic medicine.Therefore before there is good chemotherapy and gene therapy combination
Scape.
Nano medication advantage of the present invention: (1) HPMA (water wetted material) good biocompatibility, biological degradability are good.It passes through
Hydroxyl (- OH) connection PLA can form hard sphere, can also (fluorescein isothiocynate is mainly used in fluorescent antibody technics with FITC
Fluorescent dye can be combined with various antibody proteins, and the antibody in conjunction with after does not lose the specificity with certain antigen binding, and in alkali
Property solution in have strong green fluorescence) be connected；There are also its double bonds can direct and other connections with double bond.Its pair
Key can also generate gel.(2) hydrophobe drug can be carried, it is especially high to hydrophobic medicine drugloading rate.Pass through nanoprecipitation method
Preparation, obtained pharmaceutical composition is having a size of nanoscale, and narrowly distributing.In addition, the N- hydroxysuccinimidyl contained on support copolymer
Imide group can be covalently attached with the material containing amino, have the potentiality for carrying genomic medicine.Therefore there is goodization
It treats and is combined prospect with gene therapy.
Detailed description of the invention
Fig. 1 is the polylactic acid N-2- hydroxypropyl methyl third of the acrylic acid N-hydroxy-succinamide ester connection in embodiment 2
Water to form the transmission electron microscope picture of nanoparticle to the zero load of acrylamide amphipathic nature block polymer three times；
Fig. 2 is the polylactic acid N-2- hydroxypropyl methyl third of the acrylic acid N-hydroxy-succinamide ester connection in embodiment 2
Water to form the grain size distribution of nanoparticle dynamic light scattering schematic diagram to the zero load of acrylamide amphipathic nature block polymer three times.
Fig. 3 is the polylactic acid N-2- hydroxypropyl first of the connection of acrylic acid N-hydroxy-succinamide ester prepared by embodiment 7
Base acrylamide amphipathic nature block polymer contains the transmission electron microscope picture that hydrophobic drug taxol forms nanoparticle；
Fig. 4 is the polylactic acid N-2- hydroxypropyl methyl acryloyl of 7 acrylic acid N-hydroxy-succinamide ester of embodiment connection
Amine amphipathic nature block polymer contains hydrophobic drug taxol and forms nanoparticle dynamic light scattering schematic diagram.
Specific embodiment
Dynamic light scattering is carried out to multifunctional nano pharmaceutical composition obtained in following embodiment and carrier
(Zetasizer NanoZS), transmission electron microscope (U.S. FEI, Tecnai G2 20 S-TWIN, 200KV) characterization and fluorescence point
It analyses (U.S. Perkin Elmer, LS-55).
Embodiment 1
The present embodiment provides a kind of HPMA-NAS-PLA polymer and preparation method thereof:
The acrylic acid N-hydroxy-succinamide ester of the N-2- hydroxypropyhnethacrylamide of 2.8636g and 0.43g is molten
In the anhydrous DMSO of 20ml, 10mM azo-bis-iso-dimethyl is added.20 hours are stirred under conditions of 60 DEG C, it
It is poured into immediately in precipitating reagent afterwards and carries out precipitating acquisition HPMA-NAS polymer.
After step (a) is completed, the lactide of (a) the step of 0.5g HPMA-NAS polymer obtained and 30g is dissolved in
In the anhydrous middle DMSO of 25ml, 1ml triethylamine is added.It stirs 12 hours under conditions of 95 DEG C, nitrogen protection, falls immediately later
Enter in precipitating reagent and is precipitated.By obtained precipitated product with washing three times three times, puts and dry in a vacuum drying oven；It can obtain
The polylactic acid N-2- hydroxypropyhnethacrylamide amphipathic nature block polymer connected to acrylic acid N-hydroxy-succinamide ester
(HPMA-NAS-PLA polymer).
Embodiment 2
The present embodiment provides a kind of Nano medication compositions, using polymer described in embodiment 1 as carrier, with taxol
As active constituent, the active constituent is contained with the carrier and is formed.
The mass ratio of the carrier and the active constituent is 50:1.
Embodiment 3
The present embodiment provides the differences of a kind of Nano medication composition and embodiment 2 to be only that, the carrier and the work
Property ingredient mass ratio be 20:1.
Embodiment 4
The present embodiment provides the differences of a kind of Nano medication composition and embodiment 2 to be only that, the carrier and the work
Property ingredient mass ratio be 150:1.
Embodiment 5
The present embodiment provides the differences of a kind of Nano medication composition and embodiment 2 to be only that, the carrier and the work
Property ingredient mass ratio be 100:1.
Embodiment 6
The present embodiment provides the differences of a kind of Nano medication composition and embodiment 2 to be only that, the carrier and the work
Property ingredient mass ratio be 30:1.
Embodiment 7
The present embodiment provides the preparation methods of Nano medication composition as described in example 2, the specific steps are as follows:
By the poly- N-2- hydroxypropyhnethacrylamide of 20mg acrylic acid N-hydroxy-succinamide ester connection and poly- cream
Sour block copolymer is dissolved in 1ml DMSO, obtains polymer solution；
0.4mg taxol is dissolved in 0.4ml DMSO, drug solution is obtained.
The two is uniformly mixed, is then slowly added dropwise 5ml three times in water, room temperature continuing magnetic force stirs 30min.
It then is that 3500Da bag filter is dialysed with molecular weight, dialysis time 72h.
Finally with water washing three times, it is lyophilized and obtains the multifunctional nano pharmaceutical composition.
Through detecting, the polylactic acid N-2- hydroxypropyhnethacrylamide amphiphilic of acrylic acid N-hydroxy-succinamide ester connection
Property block copolymer (the HPMA-NAS-PLA polymer) contain hydrophobic drug taxol formation nanoparticle have rule
Spheroidal structure then；For particle size in 166.4 ± 3.3nm, the coefficient of dispersion is 0.129 ± 0.019.
Fig. 1 and the polylactic acid N-2- hydroxypropyl that Fig. 2 is respectively that the acrylic acid N-hydroxy-succinamide ester in embodiment 2 connects
The nanoparticle that the unloaded water three times of butylmethacrylamide amphipathic nature block polymer (HPMA-NAS-PLA polymer) is formed
The grain size distribution of transmission electron microscope picture and dynamic light scattering schematic diagram.
Fig. 3 with Fig. 4 be respectively the present embodiment prepared by the polylactic acid N- that connects of acrylic acid N-hydroxy-succinamide ester
2- hydroxypropyhnethacrylamide amphipathic nature block polymer contains the transmission electricity that hydrophobic drug taxol forms nanoparticle
Mirror figure and dynamic light scattering schematic diagram.
The method of Nano medication composition provided by embodiment 3-6 adjusts raw material/reagent according to the method for embodiment 7
Dosage can be obtained.
Test example 1
This test example provides the encapsulation rate of Nano medication composition provided by embodiment 2-5 and drugloading rate compares, such as table 1
It is shown.
Table 1
| Mass ratio | 20:1 | 50:1 | 100:1 | 150:1 |
| Drugloading rate (%) | 5.14±0.23 | 4.67±0.13 | 2.03±0.12 | 1.21±0.18 |
| Encapsulation rate (%) | 43.16±1.32 | 57.37±1.76 | 63.29±1.83 | 79.88±2.16 |
Mass ratio refers to the mass ratio of HPMA-NAS-PLA carrier Yu hydrophobic drug taxol in table 1.
Test example 2
Partial size and distribution are made using Malvern laser granulometry (ZetasizerNanoZS90) measurement embodiment 2
The particle diameter distribution of standby nano-carrier, the particle diameter distribution of prepared nano-carrier is as shown in Figure 2 as the result is shown.
The nano-carrier of Example 2 is appropriate, after steaming feedback water dilution, takes one after another drop of in the copper mesh for being covered with carbon support film
On, it places in a moment, continues that a drop 2% phosphorus dove acid progress negative staining is added dropwise, with transmission electron microscope (U.S. FEI, Tecnai
G2 20 S-TWIN, 200KV) particle shape is observed, the observed result of embodiment 1 is shown in Fig. 1.As seen from Figure 1, particle distribution is more
Uniformly, in regular spheroidal.
Test example 3
This test example provides the stability test of Nano medication composition described in embodiment 2-6.
Nanoparticle solution obtained by embodiment 2-6 is placed into 72h in 4 DEG C of refrigerators, visually observe discovery solution almost without
Variation, does not occur phenomena such as nanoparticle sedimentation, drug precipitation, detects partial size using Malvern laser granulometry, discovery is received
After grain of rice solution places 72h, partial size does not occur significant changes.
Although above having used general explanation, specific embodiment and test, the present invention is made to retouch in detail
It states, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Range.
Claims (10)
1. a kind of Nano medication composition, the active constituent including carrier and load on the carrier, which is characterized in that described
Carrier is HPMA-NAS-PLA polymer, and the active constituent is hydrophobic drug；The carrier is by acrylic acid N- hydroxysuccinimidyl
The poly- N-2- hydroxypropyhnethacrylamide HMPA of imide ester NAS connection and polylactic acid PLA obtain.
2. Nano medication composition according to claim 1, which is characterized in that the nanoparticle size is 50-
1000nm；Preferably, the nanoparticle size is 50-300nm.
3. Nano medication composition according to claim 1 or 2, which is characterized in that the carrier and the hydrophobicity medicine
The mass ratio of object is (20-150): 1；Preferably (30-60): 1；More preferably 50:1.
4. Nano medication composition according to claim 1-3, which is characterized in that the hydrophobic drug is
Taxol.
5. Nano medication composition according to claim 1-4, which is characterized in that in the HPMA-NAS-PLA
In polymer, the molar ratio of N-2- hydroxypropyhnethacrylamide and lactide is (4-8): (1-2).
6. Nano medication composition according to claim 1-5, which is characterized in that the HPMA-NAS-PLA is poly-
The weight average molecular weight for closing object is 8000-10000Da.
7. Nano medication composition according to claim 1-6, which is characterized in that described in the polymer
The poly- N-2- hydroxypropyl methyl acryloyl of acrylic acid N-hydroxy-succinamide ester connection and the mass ratio of lactide are 1:(20-
80)；It is preferred that 1:(50-70)；More preferable 1:60.
8. Nano medication composition according to claim 1-7, which is characterized in that the polymer is by with lower section
Method is prepared:
(1) N-2- hydroxypropyhnethacrylamide and acrylic acid N-hydroxy-succinamide ester are carried out under chain initiator effect
Polymerization reaction, precipitating obtain HPMA-NAS polymer；
(2) under organic amine effect, HPMA-NAS polymer is aggregated reacts to obtain HPMA-NAS- for lactide and step (1) gained
PLA polymer；
Preferably,
In step (1): the chain initiator is preferably chosen from azo-bis-iso-dimethyl AIBME, azodiisobutyronitrile AIBN
One of, more preferable azo-bis-iso-dimethyl；And/or in step (2): the organic amine is triethylamine；
It is further preferred that the mass volume ratio of the HPMA-NAS polymer and the organic amine is (0.2-1) g/1mL.
9. a kind of method for preparing the described in any item Nano medication compositions of claim 1-8, which is characterized in that will be described
HPMA-NAS-PLA polymer dissolves with the hydrophobic drug and is uniformly mixed to obtain mixed solution, adds dropwise in Xiang Sanci water
Enter the mixed solution, after dialysis freeze-drying to obtain the final product；
Preferably, include the following steps:
(a) the HPMA-NAS-PLA polymer is dissolved in organic solvent unmixing with water, obtains carrier solution；
(b) hydrophobic drug is dissolved in organic solvent unmixing with water, obtains the drug solution；
(c) carrier solution is slowly added dropwise in the drug solution；
(d) above-mentioned carrier solution and hydrophobic drug solution are added dropwise in Xiang Sanci water and obtains mixed solution；
(e) it dialyses to the mixed solution and is washed after removing organic solvent, is lyophilized to obtain the final product.
10. according to the method described in claim 9, it is characterized in that,
Step (a), in the carrier solution, the concentration of the HPMA-NAS-PLA polymer is 15-25mg/mL；
And/or
Step (b), in the drug solution, the concentration of the hydrophobic drug is 1-3mg/ml；
And/or
Step (e), for the bag filter molecular weight used of dialysing for 3000-3500Da, the time of dialysis is 65-75h.
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| CN105968370A (en) * | 2016-06-22 | 2016-09-28 | 国家纳米科学中心 | Triple disulfide-bond linked polyethylene glycol-polycaprolactone triblock copolymer as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110159113A1 (en) * | 2011-03-09 | 2011-06-30 | Mohsen Adeli | Hyperbranched polyester and a method of synthesizing a hyperbranched polyester |
| CN105968370A (en) * | 2016-06-22 | 2016-09-28 | 国家纳米科学中心 | Triple disulfide-bond linked polyethylene glycol-polycaprolactone triblock copolymer as well as preparation method and application thereof |
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