CN105853373A - Zinc oxide-based nano-drug composition, and preparation method and application thereof - Google Patents
Zinc oxide-based nano-drug composition, and preparation method and application thereof Download PDFInfo
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- CN105853373A CN105853373A CN201610191876.8A CN201610191876A CN105853373A CN 105853373 A CN105853373 A CN 105853373A CN 201610191876 A CN201610191876 A CN 201610191876A CN 105853373 A CN105853373 A CN 105853373A
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- sodium hydroxide
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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
- A61K9/1611—Inorganic compounds
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G9/00—Compounds of zinc
- C01G9/02—Oxides; Hydroxides
Abstract
The invention relates to a zinc oxide-based nano-drug composition, and a preparation method and an application thereof. The preparation method of the composition comprises the following steps: 1, mixing a sodium hydroxide and/or potassium hydroxide-alcohol solution and a zinc acetate-alcohol solution to obtain a zinc oxide colloid reaction solution; 2, taking the zinc acetate-alcohol solution, simultaneously or successively adding the zinc acetate-alcohol solution and the drug molecule-containing sodium hydroxide and/or potassium hydroxide-alcohol solution to the zinc oxide colloid reaction solution obtained in step 1; and 3, centrifuging a mixed solution obtained in step 2, removing the obtained supernatant, washing the obtained material, purifying the washed material, and drying the purified material to prepare the composition. Zinc oxide is compounded with the drug through directly using the self properties of zinc oxide and the drug, and no polymer is introduced, so the synthesis method is simple and effective. The prepared composition has good dispersibility, the hydrodynamic size is 40-90nm, and the composition has the characteristics of high bioavailability, low toxicity and degradability.
Description
Technical field
The present invention relates to nanoparticulate drug preparation technique field, be specifically related to a kind of Nano medication compositions and
Its preparation method and application, particularly relate to a kind of Nano medication compositions based on zinc oxide and preparation method thereof
And application.
Background technology
The feature that inorganic nano-particle possesses size, pattern is easily controlled, some materials have uniqueness light,
The character such as electricity, magnetic give it and have the functions such as potential imagewise development.In recent years, inorganic nano material, as
Magnetic nano-particle, mesoporous silicon oxide, material with carbon element, gold grain and quantum dot etc., carry as Nano medication
The research of body gets more and more, but the toxicological evaluation of inorganic nano material, internal metabolism process yet suffer from
Query, some potential risks toxicity (such as cytotoxicity, genotoxicity, genotoxicity etc.) limit nothing
The application clinically of machine nano material.
The design of the inorganic nano pharmaceutical carrier of some pH response types at present is expected to can solve the problem that this problem, this
A little inorganic nanoparticles can be decomposed under tumor locus acid condition, reduces inorganic material Remained mass
Interior risk.Therefore, need badly develop a kind of possess pH response degraded and the inorganic nano medicine of low toxicity characteristic
Thing transports system, utilizes the feature of the low ph value of tumor locus, improves the specific drug for tumor tissues
Release, promotes that anti-tumor drug molecule enters tumor cell, thus reduces the damage of antitumor normal tissue cell
Wound.The nano medicament carrying system possessing these good characteristics will have the most wide application prospect.
CN103622920A discloses a kind of nano-particle, its preparation method and application comprising cancer therapy drug.
Described nano-particle is bar-shaped, and described nano-particle is prepared by following technique: hydrophobic anticancer drug divided
Son is prepared as forerunner's nano-particle suspended emulsion by solvent exchange method, then by amphiphilic aqueous surfactant solution
Add described forerunner's nano-particle suspended emulsion, and the outside that supersound process obtains is coated with amphiphilic surfactant
Nano-particle；CN103550776A discloses a kind of hydrophobic drug nano-particle, its preparation method and answers
Spherical in shape or the almost spherical with, described hydrophobic drug nano-particle, described hydrophobic drug nano-particle with
Sample is that by solvent exchange method, hydrophobic drug is prepared as forerunner's nano-particle suspended emulsion, then by parents
Property aqueous surfactant solution add described forerunner's nano-particle suspended emulsion, and the outer bread that supersound process obtains
Cover the nano-particle of amphiphilic surfactant.Said medicine nano-particle all has bioavailability height and carries
The feature that dose is high, but it there is also defect in terms of drug release rate and physiological metabolism.
Zhang Zhengyong etc. have studied based on gold quantum dot, Zinc oxide quantum dot nano-functional material preparation and
Application foundation in terms of cell imaging, medicine controlled releasing is probed into and (is seen Zhang Zhengyong, " based on gold quantum dot, oxidation
The nano-functional material preparation of zinc quantum dot and the application foundation in terms of cell imaging, medicine controlled releasing thereof are visited
Study carefully ", 2013, China Ph.D. Dissertation), although it is successfully prepared into compound to zinc oxide and amycin
To nano-composition, but, what it was formed is Zinc oxide quantum dot, and particle diameter is about 3nm；And prepared
Cheng Zhongxu introduces polymer and forms ZnO polymer, finally goes bag to carry the medicines such as amycin, and synthetic method is relatively
Complexity, does not possess the characteristic of reversing tumor drug resistance.
Summary of the invention
For solving the problems referred to above of prior art, the invention provides a kind of Nano medication group based on zinc oxide
Compound and its preparation method and application.The Nano medication compositions based on zinc oxide that the present invention provides can be in acid
Selective degradation under property pH value condition, overcomes general inorganic nano-medicament carrier potential risks toxicity, carries
The high specific drug for tumor tissues discharges, and promotes anti-tumor drug molecule and enters the inverse of tumor cell
Turn tumor drug resistance.
First aspect, the invention provides the preparation method of a kind of Nano medication compositions based on zinc oxide,
It comprises the following steps:
(1) sodium hydroxide and/or potassium hydroxide-ol solution are mixed with zinc acetate-alcohol solution, obtain zinc oxide
Colloid reaction liquid；
(2) separately take zinc acetate-alcohol solution, by it with sodium hydroxide containing drug molecule and/or potassium hydroxide-
Alcoholic solution adds in the zinc oxide colloid reaction liquid that step (1) obtains jointly or successively, obtains containing load
The nano-particle mixed solution of medicine；
(3) mixed solution obtaining step (2) is centrifuged, and removes supernatant, scrubbed, purification
With dry, obtain described Nano medication compositions based on zinc oxide.
The present invention is using zinc oxide as pharmaceutical carrier, and surface is electronegative；This pharmaceutical carrier can be at acid bar
Part degraded Zn2+Ion, and Zn2+One of trace element necessary to ion human body the most just, can be by human body
Absorb, and zinc oxide is classified as one of safe material by FDA.
Heretofore described zinc oxide and medicine compound is to have directly utilized the two self character, the present invention
Synthesized Zinc oxide nanoparticle surface is electronegative, can be straight by Electrostatic Absorption with positively charged medicine
Connect compound.Without introducing polymer in preparation process, and the introducing of polymer is likely to increase pharmaceutical carrier
The toxicity of itself, and difficulty and cost prepared by pharmaceutical composition can be increased.Zinc oxide of the present invention
Nano medication preparation method of composition is the most effective；The compositions prepared has preferable dispersibility, water
Conjunction particle diameter is 40-90nm, has bioavailability height and the degradable feature of low toxicity.
The preparation principle course of reaction of the present invention is as follows:
Zn2++2OH-→Zn(OH)2↓(I)
Zn(OH)2+2OH-→Zn(OH)4 2-(II)
Zn(OH)4 2-→ZnO+2H2O+2OH-(III)
Reacted by the first step, form zinc oxide (ZnO) kernel, continue afterwards to add Zn2+Ion and 2OH-
Ion, is simultaneously introduced drug molecule, during continuously forming Zinc oxide nanoparticle growth, loads medicine
Thing molecule, ultimately forms the nano-particle of carrying medicament molecule.
According to the present invention, the preparation of step (1) described sodium hydroxide and/or potassium hydroxide-ol solution is by hydrogen
Sodium oxide and/or potassium hydroxide add in alcoholic solution, obtain through ultrasonic dissolution.Wherein, described in this step
In alcoholic solution, the method for dissolved hydrogen sodium oxide and/or potassium hydroxide is known to those skilled in the art.Except making
By the method for ultrasonic dissolution, it is also possible to the method using stirring and dissolving, concrete dissolving method does not limit.
Mass volume ratio according to the present invention, step (1) described sodium hydroxide and/or potassium hydroxide Yu alcoholic solution
For 1:(2-6), can be such as 1:2,1:2.8,1:3,1:3.2,1:3.5,1:3.8,1:4,1:4.2,1:4.5,
1:5,1:5.5 or 1:6, preferably 1:(2.5-4.5), wherein mass volume ratio can be mg/mL or g/L.
According to the present invention, the preparation of step (1) described zinc acetate-alcohol solution is to add in alcoholic solution by zinc acetate,
Obtain to dissolving through backflow, stirring.
According to the present invention, the temperature of step (1) described backflow is 40-80 DEG C, can be such as 40 DEG C, 42 DEG C,
45 DEG C, 46 DEG C, 48 DEG C, 50 DEG C, 52 DEG C, 55 DEG C, 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C, excellent
Elect 45-60 DEG C as.
According to the present invention, the time of step (1) described stirring is 1-4h, can be such as 1h, 1.2h, 1.5h,
1.8h, 2h, 2.1h, 2.5h, 2.8h, 3h, 3.2h, 3.5h, 3.8h or 4h, preferably 2-4h.
According to the present invention, step (1) described zinc acetate is 1:(2-6 with the mass volume ratio of alcoholic solution), example
As can be 1:2,1:2.2,1:2.6,1:2.8,1:3,1:3.2,1:3.5,1:3.8,1:4,1:4.6,1:5,
1:5.5 or 1:6, preferably 1:(2-4), wherein mass volume ratio can be mg/mL or g/L.
According to the present invention, the preparation method of step (2) described zinc acetate-alcohol solution and step (1) described second
The preparation method of acid zinc-ol solution is identical, does not repeats at this.
According to the present invention, the described sodium hydroxide containing drug molecule of step (2) and/or potassium hydroxide-ol are molten
The preparation of liquid is by sodium hydroxide and/or hydrogen-oxygen agent and medicine addition alcoholic solution, obtains through ultrasonic dissolution.
It is ethanol solution, aqueous isopropanol according to the present invention, step (1) and step (2) described alcoholic solution
Or any one or the mixture of at least two in ethylene glycol solution.
According to the present invention, drug molecule, sodium hydroxide and/or potassium hydroxide and alcoholic solution described in step (2)
Mass volume ratio be (1-3): 1:(2.5-4.5).
According to the present invention, described drug molecule is at least in amycin, daunorubicin or epirubicin
Kind.
According to the present invention, step (1) described sodium hydroxide and/or potassium hydroxide-ol solution are molten with zinc acetate-alcohol
The volume ratio of liquid is (2-4): 1, can be such as 2:1,2.2:1,2.3:1,2.5:1,2.8:1,3:1,3.2:1,
3.5:1,3.8:1,4:1, be preferably (2-3): 1.By controlling this volume ratio, it is possible to quickly obtain follow-up conjunction
Become the zinc oxide colloid needed for zinc-oxide nano pharmaceutical composition, there is no too much by-product production, comprehensively become
This is relatively low.
According to the present invention, step (2) described zinc acetate-alcohol solution, sodium hydroxide containing drug molecule and/
Or the volume ratio of potassium hydroxide solution and zinc oxide colloid reaction liquid is (1-3): 1:(2-5), it is preferably (1-2): 1:
(2.5-4)。
Exemplarily, the preparation method of described Nano medication compositions based on zinc oxide comprises the following steps:
(1) sodium hydroxide and/or potassium hydroxide-ol solution and zinc acetate-alcohol solution are placed in return stirring device
In with the volume ratio of 2-4:1, reflux under the conditions of 40-60 DEG C, be stirred vigorously 1-4h, obtain zinc oxide colloid anti-
Answer liquid；
(2) separately take zinc acetate-alcohol solution, add step (1) and obtain in zinc oxide colloid reaction liquid；To contain
Having the sodium hydroxide of drug molecule and/or potassium hydroxide-ol solution to be slowly added in above-mentioned reactant liquor, speed is
1-50mL/h, preferably 5-20mL/h；Above-mentioned solution refluxes under the conditions of 70-90 DEG C, is stirred vigorously, reaction
Time is 5-15h, preferably 8-12h；Afterwards, room temperature cooling, it is thus achieved that containing the nano-particle of carrying medicament
Mixed solution；
(3) mixed solution obtaining step (2) is centrifuged, and removes supernatant, uses dehydrated alcohol
Washing, the sample of purification is dried overnight at vacuum drying oven, obtains Nano medication compositions based on zinc oxide.
According to the present invention, the conventional dress that return stirring device described in step (1) can be known in the art
Put.Wherein, the preparation of zinc acetate-alcohol solution is to add in alcoholic solution by zinc acetate, and 40-80 DEG C is stirred at reflux
To dissolving.
According to the present invention, in step (2), relative to the described pharmaceutical carrier of every weight portion, described mixing medicine
The consumption of thing molecule is 0.5-2.5 weight portion.Wherein, the weight of described zinc oxide pharmaceutical carrier can be according to adding
Add zinc acetate and the mol ratio relation conversion generated between zinc oxide pharmaceutical carrier.
According to the present invention, in step (3), for step (2) obtains containing carrying medicament nanometer
The mixed solution of grain, can obtain, by repeated multiple times washing and centrifugal method, the medicament-carried nano that purity is high
Grain；Wherein, described dry method is known to those skilled in the art, except using vacuum drying oven
Beyond gained sample is dried by method, it is also possible to and reference pharmaceutics (People's Health Publisher, 2007
Publish) use the method for vacuum rotation steaming to be dried process.
In the present invention, active constituents of medicine is not particularly limited, can be known to field of medicaments personnel
Other positively charged drug molecules, such as amycin, daunorubicin and epirubicin etc..
Second aspect, present invention also offers that method prepared as described above prepares based on zinc oxide receives
Rice pharmaceutical composition.
The pharmaceutical composition that the present invention provides has (if pH value is about 7.5) under normal physiological pH value
Relatively low release amount of medicine, and the pharmaceutical composition nanometer (if pH value is about 5.0) at acidic phs
Structure is destroyed, and generates needed by human body trace elements zn2+And discharge medicine.
Heretofore described zinc oxide and medicine compound is to have directly utilized the two self character, it is not necessary to draw
Entering polymer, said composition has preferable dispersibility, and hydration particle diameter is 40-90nm, has bioavailability
Height and the degradable feature of low toxicity.
The third aspect, present invention also offers Nano medication compositions described above in preparation for treating tumor
Pharmaceutical composition in application.
Compared with prior art, the present invention at least has the advantages that
(1) present invention is the character having directly utilized zinc oxide with medicine self, is directly carried out compound system
For obtaining Nano medication compositions based on zinc oxide, it is in preparation process, it is not necessary to the introducing of polymer；
(2) the Nano medication compositions that the present invention is obtained by above-mentioned preparation method, it has good dispersion
Property, hydration particle diameter is between 40-90nm, and has bioavailability height and the degradable feature of low toxicity.
(3) the Nano medication compositions that the present invention is obtained by above-mentioned preparation method, it can be micro-at acidic cancer
Under environment, selective degradation release medicine, reduces the killing of antitumor drug normal tissue, and it also has simultaneously
There is the characteristic of reversing tumor drug resistance, effectively kill drug-resistant tumor.
Accompanying drawing explanation
Fig. 1 is the grain size distribution of the amycin Zinc oxide nanoparticle of the embodiment of the present invention 1 preparation.
Fig. 2 is the Zeta potential analysis chart of the amycin Zinc oxide nanoparticle of the embodiment of the present invention 1 preparation.
Fig. 3 is saturating under condition of different pH of amycin Zinc oxide nanoparticle of the embodiment of the present invention 1 preparation
Radio mirror figure and scanning electron microscope (SEM) photograph.
Fig. 4 is the amycin Zinc oxide nanoparticle cytotoxicity experiment result figure of the embodiment of the present invention 1 preparation.
Detailed description of the invention
Below in conjunction with accompanying drawing, the detailed description of the invention of the present invention is described in detail.Should be appreciated that this place
The detailed description of the invention described is merely to illustrate and explains the present invention, is not limited to the present invention.
For a person skilled in the art, the present invention can have various modifications and variations, all in the present invention
Spirit and principle within, any amendment, equivalent or the improvement etc. made, should be included in the present invention
Protection domain within.Experimental technique in following embodiment, if no special instructions, is conventional method；
Experiment material used, if no special instructions, is and is purchased available from routine biochemistry chemical reagent work.
Further describe the present invention by the following examples.
Embodiment 1
This example is prepared by a method comprising the following steps amycin Zinc oxide nanoparticle.
(1) zinc acetate (purchased from Aladdin company, article No. Z110780) of 27.4mg is added 72mL
In dehydrated alcohol, and it is transferred in return stirring device 50 DEG C and is stirred at reflux to dissolving that to prepare zinc acetate ethanol molten
Liquid；The sodium hydroxide of 8mg is added in 28mL dehydrated alcohol, ultrasonic make it dissolve prepared sodium hydroxide second
Alcoholic solution；Sodium hydroxide ethanol solution is added in zinc acetate ethanol solution, reflux under the conditions of 55 DEG C, acutely
Stirring 2h, obtains zinc oxide colloid reaction liquid.
(2) zinc acetate separately taking 27.4mg is dissolved in 72mL dehydrated alcohol under the conditions of as above, adds afterwards
In above-mentioned 100mL zinc oxide colloid reaction liquid, separately (will purchase containing 8mg sodium hydroxide and 20mg amycin
From Beijing Hua Fenglianbo Science and Technology Ltd.) 28mL ethanol solution slowly add with the speed of 10mL/h
Entering in above-mentioned reactant liquor, above-mentioned solution refluxes under the conditions of 80 DEG C, is stirred vigorously 10h；Afterwards, room temperature is cold
But, it is thus achieved that containing amycin Zinc oxide nanoparticle mixed solution.
(3) above-mentioned mixed solution is centrifuged, removes supernatant, use absolute ethanol washing, purification
Sample is dried overnight at vacuum drying oven, obtains the dry powder containing amycin Zinc oxide nanoparticle of the present invention.
As a comparison case, the preparation method of simple pharmaceutical carrier Zinc oxide nanoparticle and above-mentioned preparation process phase
Seemingly, differ only in preparation process, do not introduce drug molecule amycin.
Embodiment 2
This example is prepared by a method comprising the following steps amycin Zinc oxide nanoparticle.
(1) zinc acetate (purchased from Aladdin company, article No. Z110780) of 20mg is added 72mL without
In water-ethanol, and it is transferred in return stirring device 60 DEG C and is stirred at reflux to dissolving and prepares zinc acetate ethanol solution；
The sodium hydroxide of 7mg being added in 28mL dehydrated alcohol, ultrasonic to make it dissolve prepared sodium hydroxide ethanol molten
Liquid；Sodium hydroxide ethanol solution is added in zinc acetate ethanol solution, reflux under the conditions of 50 DEG C, be stirred vigorously
1.5h, obtains zinc oxide colloid reaction liquid.
(2) zinc acetate separately taking 20mg is dissolved in 72mL dehydrated alcohol in as above condition, adds above-mentioned afterwards
In 100mL zinc oxide colloid reaction liquid, separately (north will be purchased from containing 12mg sodium hydroxide and 10mg amycin
Capital Feng Lianbo Science and Technology Ltd.) 28mL ethanol solution be slowly added to the speed of 6mL/h
Stating in reactant liquor, above-mentioned solution refluxes under the conditions of 90 DEG C, is stirred vigorously 8h；Afterwards, room temperature cools down, and obtains
Amycin Zinc oxide nanoparticle mixed solution must be contained.
(3) above-mentioned mixed solution is centrifuged, removes supernatant, use absolute ethanol washing, purification
Sample is dried overnight at vacuum drying oven, obtains the dry powder containing amycin Zinc oxide nanoparticle of the present invention.
As a comparison case, the preparation method of simple pharmaceutical carrier Zinc oxide nanoparticle and above-mentioned preparation process phase
Seemingly, differ only in preparation process, do not introduce drug molecule amycin.
Embodiment 3
This example is prepared by a method comprising the following steps amycin Zinc oxide nanoparticle.
(1) zinc acetate (purchased from Aladdin company, article No. Z110780) of 35mg is added 72mL without
In water-ethanol, and it is transferred in return stirring device 50 DEG C and is stirred at reflux to dissolving and prepares zinc acetate ethanol solution；
10mg sodium hydroxide is added in 28mL dehydrated alcohol, ultrasonic makes it dissolve prepared sodium hydroxide ethanol solution；
Sodium hydroxide ethanol solution is added in zinc acetate ethanol solution, refluxes under the conditions of 60 DEG C, be stirred vigorously 4h,
Obtain zinc oxide colloid reaction liquid.
(2) zinc acetate separately taking 35mg is dissolved in 72mL dehydrated alcohol in as above condition, adds above-mentioned afterwards
In 100mL zinc oxide colloid reaction liquid, separately (north will be purchased from containing 15mg sodium hydroxide and 20mg amycin
Capital Feng Lianbo Science and Technology Ltd.) 28mL ethanol solution be slowly added to the speed of 5mL/h
Stating in reactant liquor, above-mentioned solution refluxes under the conditions of 70 DEG C, is stirred vigorously 12h；Afterwards, room temperature cools down,
Obtain containing amycin Zinc oxide nanoparticle mixed solution.
(3) above-mentioned mixed solution is centrifuged, removes supernatant, use absolute ethanol washing, purification
Sample is dried overnight at vacuum drying oven, obtains the dry powder containing amycin Zinc oxide nanoparticle of the present invention.
As a comparison case, the preparation method of simple pharmaceutical carrier Zinc oxide nanoparticle and above-mentioned preparation process phase
Seemingly, differ only in preparation process, do not introduce drug molecule amycin.
Embodiment 4
Compared with Example 1, in addition to dehydrated alcohol is replaced with aqueous isopropanol, other and embodiment 1 phase
With.
Embodiment 5
Compared with Example 1, in addition to dehydrated alcohol is replaced with ethylene glycol solution, other and embodiment 1 phase
With.
Embodiment 6
Compared with Example 1, in addition to dehydrated alcohol is replaced with isopropanol and ethylene glycol solution, other is with real
Execute example 1 identical.
Embodiment 7
Compared with Example 1, in addition to sodium hydroxide is replaced with potassium hydroxide, other is same as in Example 1.
Embodiment 8
Compared with Example 1, in addition to sodium hydroxide is replaced with sodium hydroxide and potassium hydroxide, other is with real
Execute example 1 identical.
Embodiment 9
Compared with Example 1, in addition to amycin is replaced with daunorubicin, other is same as in Example 1.
Embodiment 10
Compared with Example 1, in addition to amycin is replaced with epirubicin, other is same as in Example 1.
Testing example 1
By the laser particle analyzer of Malvern company according to the method in its description, to embodiment 1 preparation
Amycin Zinc oxide nanoparticle carries out dynamic light scattering (ZetasizerNanoZS) and measures, and records embodiment 1
The mean diameter of the nano-particle of preparation is 68nm, and has particle diameter distribution as shown in Figure 1.The knot of Fig. 1
Nano particle diameter distribution prepared by fruit explanation is the most homogeneous.
By Malvern company laser particle analyzer according to the method in its description, to preparation in embodiment 1
Nano-particle carries out Zeta-potentiometric analysis, records the nano-particle mean charge of preparation in embodiment 1 and is
-7.63mV (such as Fig. 2), shows that it is with faint negative charge.
The pharmaceutical composition preparing embodiment 2-10 carries out the most identical test, and its result is as shown in table 1.
Table 1
Testing example 2
Use S4800 scanning electron microscope and the Tecnai G20 of FEI Co. of Hitachi company respectively
S-TWIN transmission electron microscope, according to the method in its description, observes the amycin oxygen of embodiment 1 preparation
Change zinc nanoparticles shape characteristic respectively when neutrallty condition pH7.5 and acid condition pH5.0, such as Fig. 4
Shown in, nano-particle pattern rounded granule during neutrallty condition pH7.5, and when acid condition pH5.0,
Nanoparticle structure is destroyed, and complete nano-particle is difficult to found.Result shows, above-mentioned comprise Ah
The Zinc oxide nanoparticle of mycin can reach when pH5.0 to discharge rapidly, and rate of release and burst size are far away
It is higher than under conditions of pH7.5, thus the above-mentioned Zinc oxide nanoparticle comprising amycin has pH sensitivity
Drug release characteristics.
The pharmaceutical composition preparing embodiment 2-10 carries out the most identical test, obtains and as above basic phase
Same testing result, the present invention does not repeats them here.
Testing example 3
People source drug-resistant type breast cancer cell MCF-7R and responsive type breast cancer cell MCF-7S is selected to examine respectively
Survey the cytotoxicity comprising amycin Zinc oxide nanoparticle of preparation in embodiment 1.According to document (" cell
Cultivate ", Si Tuzhenqiang, world book publishing company, 1996) in method above-mentioned cell is trained
Supporting, then add embodiment 1 preparation comprises amycin Zinc oxide nanoparticle, according to literary composition after dosing 48h
Offer the method (MTT in (" cell cultivation ", Si Tuzhenqiang, world book publishing company, 1996)
Method) detection cell survival rate, this is nano-particle experimental group.Positive control be containing same concentrations free Ah
Mycin medicine group, negative control is the blank cultures without cancer therapy drug, wherein with thin in negative control group
The survival rate of born of the same parents is by 100% calculating.Nano-particle in embodiment 1 and positive control are to MCF-7R cell
Distinguish the most as shown in Figure 4 with the killing situation of MCF-7S cell.Result shows, the nanometer in embodiment 1
Grain is above positive control, especially at drug-resistant type to the fragmentation effect of MCF-7R cell and MCF-7S cell
Show the most prominent on breast cancer cell MCF-7R, embody amycin Zinc oxide nanoparticle and there is reverse
The characteristic of drug resistance.Add the concentration of medicine with the densitometer of amycin, respectively 0.001,0.01,0.1,
1,10 and 100 μ g/mL；Nano-particle is for the half survival concentration of MCF-7R cell
(IC50=0.42 μ g/mL) significantly lower than the half survival concentration (IC of free amycin50>100μg/mL).?
In MCF-7S cell, the IC of nano-particle50It is 0.47 μ g/mL, hence it is evident that less than the IC of free amycin50
It is worth 2.58 μ g/mL.
The pharmaceutical composition preparing embodiment 2-10 carries out the most identical test, and it is respectively at MCF-7S
In cell and MCF-7R cell, the IC of nano-particle50Result is as shown in table 2-3.
Table 2
Table 3
The preferred embodiment of the present invention described in detail above, but, the present invention is not limited to above-mentioned enforcement
Detail in mode, in the technology concept of the present invention, can enter technical scheme
The multiple simple variant of row, these simple variant belong to protection scope of the present invention.
It is further to note that each the concrete technical characteristic described in above-mentioned detailed description of the invention,
In the case of reconcilable, can be combined by any suitable means, in order to avoid unnecessary weight
Multiple, various possible compound modes are illustrated by the present invention the most separately.
Additionally, combination in any can also be carried out between the various different embodiment of the present invention, as long as it is not
Running counter to the thought of the present invention, it should be considered as content disclosed in this invention equally.
Claims (10)
1. the preparation method of a Nano medication compositions based on zinc oxide, it is characterised in that include with
Lower step:
(1) sodium hydroxide and/or potassium hydroxide-ol solution are mixed with zinc acetate-alcohol solution, obtain zinc oxide
Colloid reaction liquid；
(2) separately take zinc acetate-alcohol solution, by it with sodium hydroxide containing drug molecule and/or potassium hydroxide-
Alcoholic solution adds in the zinc oxide colloid reaction liquid that step (1) obtains jointly or successively, obtains containing load
The nano-particle mixed solution of medicine；
(3) mixed solution obtaining step (2) is centrifuged, and removes supernatant, scrubbed, purification
With dry, obtain described Nano medication compositions based on zinc oxide.
2. preparation method as claimed in claim 1, it is characterised in that step (1) described sodium hydroxide
And/or the preparation of potassium hydroxide-ol solution is to add in alcoholic solution by sodium hydroxide and/or potassium hydroxide, through super
Sound dissolves and obtains；
Preferably, the mass volume ratio of described sodium hydroxide and/or potassium hydroxide and alcoholic solution is 1:(2-6),
It is preferably 1:(2.5-4.5)；
Preferably, any one during described alcoholic solution is ethanol solution, aqueous isopropanol or ethylene glycol solution
Or the mixture of at least two.
3. preparation method as claimed in claim 1 or 2, it is characterised in that step (1) and (2) institute
The preparation stating zinc acetate-alcohol solution is to add in alcoholic solution by zinc acetate, obtains to dissolving through backflow, stirring
Arrive；
Preferably, the temperature of described backflow is 40-80 DEG C, preferably 45-60 DEG C；
Preferably, described zinc acetate is 1:(2-4 with the mass volume ratio of alcoholic solution)；
Preferably, any one during described alcoholic solution is ethanol solution, aqueous isopropanol or ethylene glycol solution
Or the mixture of at least two.
4. the preparation method as described in one of claim 1-3, it is characterised in that step (1) described oxygen
The preparation changing zinc colloid is sodium hydroxide and/or potassium hydroxide-ol solution to be mixed with zinc acetate-alcohol solution, warp
Reflux, stir and obtain；
Preferably, the temperature of described backflow is 40-90 DEG C, preferably 45-65 DEG C；
Preferably, the time of described stirring is 1-4h, preferably 2-4h；
Preferably, described sodium hydroxide and/or potassium hydroxide-ol solution with the volume ratio of zinc acetate-alcohol solution are
1:(2-4)。
5. the preparation method as described in one of claim 1-4, it is characterised in that step contains described in (2)
Having the sodium hydroxide of drug molecule and/or the preparation of potassium hydroxide-ol solution is by sodium hydroxide and/or hydroxide
Potassium and medicine add in alcoholic solution, obtain through ultrasonic dissolution；
Preferably, described drug molecule, sodium hydroxide and/or potassium hydroxide with the mass volume ratio of alcoholic solution are
(1-3):1:(2.5-4.5)；
Preferably, at least one during described drug molecule is amycin, daunorubicin or epirubicin.
6. the preparation method as described in one of claim 1-5, it is characterised in that step (3) is described negative
The preparation of the nano-particle mixed solution of medicine carrying thing is by the sodium hydroxide containing drug molecule and/or hydroxide
Potassium-ol solution adds zinc oxide colloid reaction liquid, obtains through backflow, stirring；
Preferably, the temperature of described backflow is 70-90 DEG C, preferably 75-85 DEG C；
Preferably, the time of described stirring is 5-15h, preferably 8-12h；
Preferably, described sodium hydroxide containing drug molecule and/or potassium hydroxide-ol solution add speed and are
1-50mL/h, preferably 5-20mL/h；
Preferably, described sodium hydroxide containing drug molecule and/or potassium hydroxide-ol solution and zinc oxide colloid
The volume ratio of reactant liquor is 1:(2-4).
7. the preparation method as described in one of claim 1-6, it is characterised in that comprise the following steps:
(1) sodium hydroxide and/or potassium hydroxide-ol solution and zinc acetate-alcohol solution are placed in return stirring device
In with (2-4): the volume ratio of 1, under the conditions of 40-60 DEG C reflux, stir 1-4h, obtain zinc oxide colloid anti-
Answer liquid；
(2) separately take zinc acetate-alcohol solution, be first added into the zinc oxide colloid reaction liquid that step (1) obtains
In；Again the sodium hydroxide containing drug molecule and/or potassium hydroxide-ol solution are added with the speed of 1-50mL/h
Enter in above-mentioned reactant liquor；Reflux under the conditions of 70-90 DEG C, stirring, react 5-15h, cool down through room temperature, obtain
Must be containing the nano-particle mixed solution of carrying medicament；
(3) mixed solution obtaining step (2) is centrifuged, and removes supernatant, uses dehydrated alcohol
Washing, purification, and be dried overnight, obtain described Nano medication compositions based on zinc oxide.
8. preparation method as claimed in claim 7, it is characterised in that step (2) described zinc acetate-alcohol
Solution is 1:(3-5 with the volume ratio of zinc oxide colloid reaction liquid)；
Preferably, described in step (3), sample drying method uses vacuum rotation to steam or vacuum drying oven is done after purification
Dry.
9. Nano medication based on the zinc oxide combination that the preparation method as described in one of claim 1-8 obtains
Thing；Preferably, the hydration particle diameter of described Nano medication compositions is 40-90nm.
10. Nano medication compositions as claimed in claim 9 is used for treating the drug regimen of tumor in preparation
Application in thing.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653241A (en) * | 2018-06-27 | 2018-10-16 | 黑龙江大学 | A kind of preparation method of anticancer drug nanoparticle |
| CN109512800A (en) * | 2019-01-18 | 2019-03-26 | 沈阳药科大学 | A kind of preparation method carrying medicine zinc oxide silica composite nano-granule |
| CN114886871A (en) * | 2022-04-15 | 2022-08-12 | 北京林业大学 | Construction and preparation method of self-driven drug carrier |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550776A (en) * | 2013-10-31 | 2014-02-05 | 国家纳米科学中心 | Hydrophobic drug nanoparticles as well as preparation method and application thereof |
| CN103622920A (en) * | 2013-11-29 | 2014-03-12 | 国家纳米科学中心 | Nanoparticles containing anti-cancer drugs and preparation method and application thereof |
| CN104548108A (en) * | 2015-02-02 | 2015-04-29 | 哈尔滨工业大学 | Preparation method of mesoporous apatite nano drug carrier with pH responsive core-shell structure |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103550776A (en) * | 2013-10-31 | 2014-02-05 | 国家纳米科学中心 | Hydrophobic drug nanoparticles as well as preparation method and application thereof |
| CN103622920A (en) * | 2013-11-29 | 2014-03-12 | 国家纳米科学中心 | Nanoparticles containing anti-cancer drugs and preparation method and application thereof |
| CN104548108A (en) * | 2015-02-02 | 2015-04-29 | 哈尔滨工业大学 | Preparation method of mesoporous apatite nano drug carrier with pH responsive core-shell structure |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653241A (en) * | 2018-06-27 | 2018-10-16 | 黑龙江大学 | A kind of preparation method of anticancer drug nanoparticle |
| CN109512800A (en) * | 2019-01-18 | 2019-03-26 | 沈阳药科大学 | A kind of preparation method carrying medicine zinc oxide silica composite nano-granule |
| CN114886871A (en) * | 2022-04-15 | 2022-08-12 | 北京林业大学 | Construction and preparation method of self-driven drug carrier |
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