CN103191019B - Method for preparing hydrophobic drug nanoparticles by ice template method - Google Patents
Method for preparing hydrophobic drug nanoparticles by ice template method Download PDFInfo
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- CN103191019B CN103191019B CN201310130901.8A CN201310130901A CN103191019B CN 103191019 B CN103191019 B CN 103191019B CN 201310130901 A CN201310130901 A CN 201310130901A CN 103191019 B CN103191019 B CN 103191019B
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Abstract
The invention discloses a method for preparing hydrophobic drug nanoparticles by the ice template method. The method includes following steps: 1), preparing an ice template; 2), preparing nanoparticles: enabling drugs to be prepared into a solution at corresponding concentration in organic solvent, dropwise adding the solution on the ice template prepared in former step, and freezing after the organic solvent is volatilized; 3), removing the ice template, and enabling ice to be melted; and 4), collecting the nanoparticles: subjecting liquid obtained by melting in the step 3) to ultrasonic treatment to obtain monodispersed nanoparticles uniform in size. The method for preparing nanodrugs is simple in operation, low in cost, high in yield, adjustable in composition and proportion of the nanodrugs, small and uniform in size of the nanodrugs, free of environment pollution, and free of side effect during template removal, provides material basis and technical guarantee for development and application research of new-generation anticancer drug preparations with high drug-loading capacity, can be used in the field of cancer diagnosis and treatment, and has wide application prospect.
Description
Technical field
The present invention relates to a kind of method of preparing cancer therapy drug molecular nanostructure, particularly relate to and a kind ofly using ice and as template, prepare the method for hydrophobic medicament nano granule.
Background technology
At present, cancer has become the second largest killer of human health, and wherein chemotherapy is topmost treatment means.But there are a lot of side effect in chemotherapy, most cancer therapy drug poorly water-soluble, to the poor selectivity of tumor tissues, curative effect is low, side effect is large.In order to increase anticancer effect and to reduce toxic and side effects, the many scientists in the whole world competitively research and develop state-of-the art nano-medicament carrier material and technology, comprise the cancer diagnosis at initial stage, tumor-localizing accurately, to lesions position, accurately carry and in the real-time body of cancer therapy drug, medicine performance curative effect, monitor etc., to fundamentally change the situation of current cancer diagnosis, treatment and prevention.
Along with the constantly bringing forth new ideas and attempting of scientific domain, in recent years, many medicament nano systems based on carrier have been developed.The existence of carrier in nanoparticle system, has brought a series of corresponding problems.For example, the weight of carrier, often far above the weight of the drug molecule loading, makes carrier in drug particles account for weight greatly, causes the drug loading of whole composite particles system low; In the process of design medicine nano-particle, carrier tends to bring the problems such as bio-toxicity and internal metabolism; In addition, although carrier can well be coated medicine wherein, also brought that desorption difficulty, synthetic cost are high and consuming time simultaneously, multicomponent pharmaceutical or image-forming contrast medium be difficult to enter the problems such as same dosage form, these problems make the selection of carrier and the design of the granule difficulty that becomes.Generally, the drug material of selecting carrier to load is all the material of good water solubility, but most of fat-soluble medicine strong, poorly water-soluble is difficult to the mode that adopts carrier to load, and makes this preparation method have certain limitation.
In sum, how designing suitable a, avirulence, desorption ability is strong, drug loading is high and universality is strong medicament nano structure, is a very important research direction.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of ice template legal system for the method for hydrophobic drug nano-particle, and prepared Nano medication has excellent active anticancer.
The technical solution used in the present invention is to provide a kind of ice template legal system for the method for hydrophobic drug nano-particle, and the method comprises the steps:
1) prepare ice template: water is poured in container, then by the freezing rear taking-up of container, obtained ice template;
2) preparation of nano-particle: medicine is mixed with in organic solvent to the solution of respective concentration, is added drop-wise on the ice template that step makes, treat that organic solvent vapors away, more freezing;
3) remove template: by step 2) in ice template after again freezing take out, ice template melts as liquid, or puts into freeze drying box and remove solid ice;
4) collect nano-particle: the liquid water supersound process that step 3) is melted; Or the powder taking out in freeze drying box is added to the water, can obtains the nanoparticle of monodispersed size homogeneous.
Preferably, the size of ice template described in step 1) depends on container dimensional used.
Preferably, cooling time described in step 1) is 5-24h, and cryogenic temperature is-5 ℃～-20 ℃.
Preferably, medicine step 2) is selected from one or more hydrophobic medicines or hydrophobic image-forming contrast medium.
Preferably, described hydrophobic medicine is teniposide, curcumin or Ismipur.
Preferably, step 2) described organic solvent is selected from oxolane, methanol or acetone.
Preferably, solution concentration step 2) is 0.5mM-20mM or is never saturated to the arbitrary concentration between saturated concentration.
Preferably, step 2) described in, cooling time is 5-24h, and cryogenic temperature is-5 ℃～-20 ℃.
Preferably, the pattern of nanoparticle described in step 4) is octahedra, and the size of nanoparticle is 10nm～1 μ m.
Preferably, the thawing of ice template described in step 3) refers to ice distillation under the direct thawing of room temperature or vacuum.
The invention has the beneficial effects as follows: (1) experiment condition is gentle, simple to operate, does not need to use a large amount of toxic solvents and additive, do not need complicated synthetic and preparation process; (2) ice is as template, more can not bring any side effect in the process of removing; (3) output is high and controlled; (4) wide application, is applicable to various hydrophobic medicine and hydrophobic image-forming contrast medium.Therefore, the present invention be a kind of simple to operate, cost is low, productive rate is high, Nano medication component and ratio is adjustable, size is little and homogeneous, environmentally safe, removing template process have no side effect Nano medication preparation method, for the development of the anti-cancer drug preparation of high drug load of new generation and applied research provides material base and technical guarantee, can be used for cancer diagnosis and treatment field, be with a wide range of applications.
Accompanying drawing explanation
Fig. 1 is weighing botle optical photograph front elevation A and the side view B that fills ice template;
Fig. 2 is the standby teniposide of ice template legal system (VM-26) Nano medication different-shape SEM picture;
Fig. 3 is the dynamic light scattering picture (DLS) with standby teniposide (VM-26) the Nano medication particle of ice template legal system;
Fig. 4 is the SEM picture A. tetrapyridylporphine (H of other standby several hydrophobic anticancer drugs of ice template legal system and image-forming contrast medium
2tPyP); B. curcumin (CCM); C.6-purinethol (6-MP); D. paclitaxel (PTX)+teniposide (VM-26) two-component nanoparticles
The specific embodiment
Below in conjunction with drawings and Examples, the present invention is further illustrated.
Embodiment 1
Ice template legal system is for the method for cancer therapy drug teniposide (VM-26) nano-particle, method is as follows: 1) prepare ice template: get weighing botle or culture dish, add 5mL high purity water, putting into refrigerator and cooled freezes, cryogenic temperature is-5 ℃, after freezing 5h, take out, and by ice layer broken powder ice powder end blow away, form ganoid ice template;
2) preparation of medicament nano granule: hydrophobic anticancer drug teniposide (VM-26) is dissolved in oxolane (THF), be made into the solution of 10mM, with disposable dropper, take a morsel and dropwise drip to ice template surface, and repeatedly blow with ear washing bulb, lower boiling organic solvent THF is vapored away fast, repeat this operation 3 times, finally put it into freezer compartment of refrigerator 24h, cryogenic temperature is-5 ℃;
3) remove template: after 24h, ice template is taken out from refrigerator, directly it is at room temperature melted as liquid;
4) collect nano-particle: the liquid melting in step 3) is carried out to supersound process 5min, obtain the medicament nano particle of monodispersed size homogeneous.
Embodiment 2
Standby tetrapyridylporphine (the H that can be used as fluorescence imaging contrast agent of ice template legal system
2tPyP) method of nano-particle, method is as follows:
1) prepare ice template: get weighing botle or culture dish, add 5mL high purity water, put into refrigerator and cooled and freeze, cryogenic temperature is-10 ℃, after freezing 10h, take out, and by ice layer broken powder ice powder end blow away, form ganoid ice template;
2) preparation of medicament nano granule: by hydrophobicity tetrapyridylporphine (H
2tPyP) be dissolved in oxolane (THF), be made into the solution of 10mM, with disposable dropper, take a morsel and dropwise drip to ice template surface, and repeatedly blow with ear washing bulb, lower boiling organic solvent tetrahydrofuran is vapored away fast, repeat this operation 3 times, finally put it into freezer compartment of refrigerator 15h, cryogenic temperature is-10 ℃;
3) remove template: after 15h, ice template is taken out from refrigerator, directly it is at room temperature melted as liquid;
4) collect nano-particle: the liquid melting in step 3) is carried out to supersound process 5min, obtain the medicament nano particle of monodispersed size homogeneous.
Embodiment 3
Ice template legal system is for the method for cancer therapy drug curcumin (CCM) nano-particle, and method is as follows:
1) prepare ice template: get weighing botle or culture dish, add 5mL high purity water, put into refrigerator and cooled and freeze, cryogenic temperature is-15 ℃, after freezing 24h, take out, and by ice layer broken powder ice powder end blow away, form ganoid ice template;
2) preparation of medicament nano granule: hydrophobic anticancer drug curcumin (CCM) is dissolved in acetone, be made into the solution of 1.5mM, with disposable dropper, take a morsel and dropwise drip to ice template surface, and repeatedly blow with ear washing bulb, lower boiling organic solvent-acetone is vapored away fast, repeat this operation 5 times, finally put it into freezer compartment of refrigerator 5h, cryogenic temperature is-15 ℃;
3) remove template: after 5h, ice template is taken out from refrigerator, put into freeze dryer, ice, because sublimation is removed, is only left pulverous medicament nano granule;
4) collect nano-particle: after removing solid ice, then add 5mL high purity water in pulverous medicament nano granule, obtain the medicament nano particle of monodispersed size homogeneous.
Embodiment 4
Ice template legal system is for the method for Anticancer Drug 6-Mercaptopurine (6-MP) nano-particle, and method is as follows:
1) prepare ice template: get weighing botle or culture dish, add 5mL high purity water, put into refrigerator and cooled and freeze, cryogenic temperature is-20 ℃, after freezing 15h, take out, and by ice layer broken powder ice powder end blow away, form ganoid ice template;
2) preparation of medicament nano granule: hydrophobic anticancer drug Ismipur (6-MP) is dissolved in methanol, be made into the solution of 2mM, with disposable dropper, take a morsel and dropwise drip to ice template surface, and repeatedly blow with ear washing bulb, lower boiling organic solvent methanol is vapored away fast, repeat this operation 3 times, finally put it into freezer compartment of refrigerator 20h, cryogenic temperature is-20 ℃;
3) remove template: second day is taken out ice template from refrigerator, directly it is at room temperature melted as liquid;
4) collect nano-particle: the liquid that upper step is melted carries out supersound process 5min; Obtain the medicament nano particle of monodispersed size homogeneous.
Embodiment 5
Ice template legal system is for the method for anti-cancer medicine paclitaxel (PTX)+teniposide (VM-26) bi-component nano-particle, and method is as follows:
1) prepare ice template: get weighing botle or culture dish, add 5mL high purity water, put into refrigerator and cooled and freeze, cryogenic temperature is-20 ℃, after freezing 20h, take out, and by ice layer broken powder ice powder end blow away, form ganoid ice template;
2) preparation of medicament nano granule: hydrophobic anticancer drug teniposide (VM-26) and paclitaxel (PTX) are dissolved in respectively in oxolane (THF), respectively be made into the solution of 10mM, with 1 to 1 ratio, be made into mixed solution again, with disposable dropper take a morsel mix after solution dropwise drip to ice template surface, and repeatedly blow with ear washing bulb, lower boiling organic solvent tetrahydrofuran is vapored away fast, repeat this operation 3 times, finally put it into freezer compartment of refrigerator 20h, cryogenic temperature is-20 ℃;
3) remove template: after 20h, ice template is taken out from refrigerator, directly it is at room temperature melted as liquid;
4) collect nano-particle: the liquid melting in step 3) is carried out to supersound process 5min, obtain the medicament nano particle of monodispersed size homogeneous.
Each cited raw material of the present invention can be realized the present invention, and the bound value of each raw material and experiment parameter, interval value can realize the present invention, at this, does not enumerate embodiment.
Medicament nano structure and morphology prepared by embodiment 1-5 as shown in Figures 2 and 4.
Fig. 3 shows that the nano-particles size average diameter of preparation is 226.2nm, shows that the granule of preparation is nano-particle.
Claims (7)
1. ice template legal system, for a method for hydrophobic drug nano-particle, is characterized in that, comprises the steps:
1) prepare ice template: water is poured in container, then after container is freezing, ice is taken out, obtain ice template;
2), on the ice template preparation of nano-particle: medicine is mixed with in organic solvent to the solution of respective concentration, is added drop-wise to step 1) making, treat that organic solvent vapors away, again freezing;
3) remove template: by step 2) in ice template after again freezing take out, ice template melts as liquid, or puts into freeze drying box and remove solid ice;
4) collect nano-particle: by step 3) the liquid water supersound process of melting or the powder taking out in freeze drying box is added to the water, can obtain the nanoparticle of monodispersed size homogeneous,
Wherein, step 1) described in, cooling time is 5-24h, and cryogenic temperature is-5 ℃～-20 ℃; Step 2) described organic solvent is selected from oxolane, methanol or acetone; Described respective concentration is 0.5mM-20mM; Described cooling time is 5-24h, and cryogenic temperature is-5 ℃～-20 ℃
2. ice template legal system according to claim 1, for the method for hydrophobic drug nano-particle, is characterized in that: step 1) described in the size of ice template depend on container dimensional used.
3. ice template legal system according to claim 1, for the method for hydrophobic drug nano-particle, is characterized in that: step 2) described medicine is selected from one or more hydrophobic medicines.
4. ice template legal system according to claim 1, for the method for hydrophobic drug nano-particle, is characterized in that: step 2) described medicine is selected from one or more hydrophobic image-forming contrast mediums.
5. ice template legal system according to claim 3, for the method for hydrophobic drug nano-particle, is characterized in that: described hydrophobic medicine is teniposide, curcumin or Ismipur.
6. ice template legal system according to claim 1, for the method for hydrophobic drug nano-particle, is characterized in that: step 4) described in the pattern of nanoparticle for octahedra, the size of nanoparticle is 10nm～1 μ m.
7. ice template legal system according to claim 1, for the method for hydrophobic drug nano-particle, is characterized in that: step 3) described in ice template melt and to refer to that room temperature directly melts, described in put into freeze drying box and remove solid ice and refer to ice distillation under vacuum.
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| US10085942B2 (en) * | 2015-11-19 | 2018-10-02 | City University Of Hong Kong | Nanoparticles, method of preparing the same and their use |
| US20210393541A1 (en) * | 2020-06-19 | 2021-12-23 | City University Of Hong Kong | Preparation of nanoparticles using modified ice-template |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2328154A (en) * | 1997-09-03 | 1999-02-17 | Asoka Malinga Ratwatte Hiran | A method of tabletting comprising forming a mixture, containing active agent & free-flowing ice particles, into a tablet & removing the ice from the tablet |
| CN1850120A (en) * | 2006-02-28 | 2006-10-25 | 华南理工大学 | Cold concentration method for water extraction liquid of traditional Chinese herbs |
| CN101293783A (en) * | 2007-04-25 | 2008-10-29 | 中国科学院理化技术研究所 | Method for preparing inorganic stephanoporate composite material with freeze dehydration |
| CN101785877A (en) * | 2010-04-07 | 2010-07-28 | 华中科技大学 | Method for preparing bionic composite material with lamellar multilevel structure |
| TW201235035A (en) * | 2011-02-16 | 2012-09-01 | Univ China Medical | Dehydration and concentration method of traditional Chinese medicine decoction |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2008174505A (en) * | 2007-01-19 | 2008-07-31 | Advance Co Ltd | Method for producing lyophilized product |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2328154A (en) * | 1997-09-03 | 1999-02-17 | Asoka Malinga Ratwatte Hiran | A method of tabletting comprising forming a mixture, containing active agent & free-flowing ice particles, into a tablet & removing the ice from the tablet |
| CN1850120A (en) * | 2006-02-28 | 2006-10-25 | 华南理工大学 | Cold concentration method for water extraction liquid of traditional Chinese herbs |
| CN101293783A (en) * | 2007-04-25 | 2008-10-29 | 中国科学院理化技术研究所 | Method for preparing inorganic stephanoporate composite material with freeze dehydration |
| CN101785877A (en) * | 2010-04-07 | 2010-07-28 | 华中科技大学 | Method for preparing bionic composite material with lamellar multilevel structure |
| TW201235035A (en) * | 2011-02-16 | 2012-09-01 | Univ China Medical | Dehydration and concentration method of traditional Chinese medicine decoction |
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