CN104434807B - Taxol and its homologue solid dispersions nanoparticle and preparation method thereof - Google Patents
Taxol and its homologue solid dispersions nanoparticle and preparation method thereof Download PDFInfo
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- CN104434807B CN104434807B CN201410629097.2A CN201410629097A CN104434807B CN 104434807 B CN104434807 B CN 104434807B CN 201410629097 A CN201410629097 A CN 201410629097A CN 104434807 B CN104434807 B CN 104434807B
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Abstract
The present invention relates to taxol and its homologue solid dispersions nanoparticle and preparation method thereof, using poloxamer as carrier, the assistant carrier for forming nanoparticle is used as using zinc salt, taxol or its homologue are supported on above-mentioned carrier, wherein the content of taxol or its homologue is 4.5~20wt%, the size distribution of nanoparticle is in 50~250nm, after raw material mixes scattered, vaporization at high temperature solvent, freezing, at room temperature plus water ultrasonic disperse filters the nanoparticle for producing taxol or its homologue solid dispersions.The taxol and its nanoparticle of homologue solid dispersions that the present invention is prepared are compared with presently commercially available injection (Taxol), tumour inhibiting rate after the oral and injection of the nanoparticle is suitable with commercially available prod, and improves security of the medicine in clinical practice.
Description
Technical field
The invention belongs to medical field of nanometer technology, is received more particularly, to a kind of taxol and its homologue solid dispersions
Grain of rice and preparation method thereof.
Background technology
Taxol (Paclitaxel) and its homologue are isolated one from Chinese yew genus plants yewtree
The baroque diterpenoids compound of kind.As a kind of new microtubule stabilizer, it is referred to as by National Cancer research center
For the most great breakthrough in chemical therapy field in past 15-20.Taxol and its homologue are current clinical practices
Treat one of medicine.It is mainly used in treating oophoroma, breast cancer, melanoma and non-small cell lung cancer etc..Its mechanism of action is to promote
Enter micro-pipe dimer and be assembled into micro-pipe, and can prevent micro-pipe from decomposing and making microtubule stabilization, reach the effect of histocyte division
Fruit.
Although taxol and its homologue all have an excellent antitumor activity, its solubility in water is smaller.
According to the literature, taxol and its homologue have the lipophilicity of height, and not soluble in water (solubility in water is 0.006mg/
Ml), insoluble in petroleum ether, the organic solvents such as methanol, ethanol, ethyl acetate, dichloromethane, dimethyl sulfoxide (DMSO) are dissolved in.Japanese yew
The extremely low water solubility of alcohol and its homologue brings very big difficulty to intravenously administrable.To solve this problem, people are in injection
Add surfactant polyoxyethylene castor oil (Cremophor EL).The formulation for paclitaxel (Taxol) clinically used at present
Taxol is exactly dissolved in Emulsifier EL-60 with the mixed liquor of absolute ethyl alcohol 1: 1, preceding physiological saline or 5% Portugal is administered
Grape liquid glucose dilutes.A series of filters are needed to use in medication, to prevent from some little particles being injected in vivo.It is and compound molten
Histamine can be discharged during Emulsifier EL-60 degradation in vivo in agent, so as to which serious allergic reaction occur.So state of the U.S.
Vertical Cancer Institute recommends 24 hours medicines for giving antiallergic action before using Taxol, as use in advance cortex alcohols (
Sai meter Song), diphenhydramine and bisfentidine (Cimetidine, ranitidine) etc..It is whole and administration process needs strict monitoring
Individual process is extremely inconvenient.Other homologues such as Docetaxol injection using a large amount of Tween-80s because bringing serious allergy
Reaction.
Therefore, it is necessary to the formulation of traditional taxol and its homologue is transformed.Scientist is mainly focused on elimination
Solubility, the stability of adverse reaction, increase taxol and its homologue, keep away caused by ethoxylate castor oil and Tween-80
Exempt from allergic reaction without influenceing antitumor activity, reducing toxicity etc. to deploy to study.
To reduce taxol and its general toxicity of homologue and the toxic side effect of solvent, in recent years, people are to taxol
And its formulation of homologue has carried out a large amount of and in-depth study.One is in order to improve taxol and its homologue in water
Solubility.People have carried out substantial amounts of research in terms of taxol and its homologue soluble derivative, such as soluble hemizygous
Into paclitaxel derivatives, the prodrug that taxol is made in some water soluble groups is connected on taxol, to improve the water of taxol
Dissolubility (patent publication No. KR20070071027A).This prodrug forms can in physiological conditions hydrolyze and discharge Japanese yew
Alcohol.But this prodrug is general unstable in vivo, and can also influence its drug effect to a certain extent, thus also without commercially available production
Product;The second is taxol and its homologue be made into targeting preparation, improve concentration of the medicine in tumor locus, reduce blood and its
Drug concentration in its tissue, not only increases curative effect, can also reduce whole body toxic side effect.Typically use liposome at present
(patent publication No. CN1391891A), microballoon (patent publication No. is US2004092577 (A1)), magnetic nanoparticle
(CN1994291A), the mode such as emulsion (patent publication No. CN1416810A) and vesica (CN1303994C) prepares taxol
Targeting preparation.But most of targeting preparations are still in the experimental study stage at present, also many problems have it is to be solved, such as fat
The shortcomings of medicine easy to leak and undesirable Targeting distribution be present in plastid targeted system;The particle diameter distribution of microballoon is uneven, it is impossible to directly
Drug delivery to target tissue, it is generally used for chemoembolization and local injection etc..
Recently, U.S. FDA approval albumin-bound paclitaxel nanoparticle injection suspension listing, for metastatic breast cancer
After combined chemotherapy failure or breast cancer that NACT is recurred in 6 months.This product is by albumin-bound paclitaxel nanoparticle group
Into without organic solvent, therefore dosage is bigger than Taxol, therefore can strengthen antitumor action.In addition, albumin is to normal
The protein of cell infusion nutrition, studies have shown that it put aside in the tumour of fast-growth.Thus, effect of nano-paclitaxel injection
Suspension has the effect of preferable.But because the cost of albumin is higher, heavy financial burden is brought to patient.
Pluronic is amphipathic block copolymer, is PEO-PPO-PEO three blocks.In a solvent PEO can and gold
Category ion is coordinated, and hydrophobic drug is wrapped in into PPO hydrophobic regions, not only improves medicine stability, and the parent in shell
Water-based PEO can be avoided being identified by human body reticuloendothelial system and captured, and extend circulation time in blood, appropriate control grain
Footpath can realize the passive target in tumor locus.And pluronic copolymer is by reducing P glycoprotein after internalization medicine
Outer row acts on and reduces the multidrug resistance of antineoplastic.Therefore pluronic copolymer is due to its biodegradability, life
Thing compatibility and it is amphipathic the features such as, have in terms of hydrophobic drug is conveyed uniqueness advantage.
The content of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of simplicity is easy to get, quality
Nanoparticle of stable and hypotoxicity taxol and its homologue solid dispersions and preparation method thereof.The nanoparticle can increase purple
China fir alcohol and its homologue stability, and circulation time in vivo can be extended, so as to more passive targets in tumor tissues,
Improve therapeutic effect.
The purpose of the present invention can be achieved through the following technical solutions:
Taxol and its homologue solid dispersions nanoparticle, the nanoparticle using poloxamer as carrier, using zinc salt as
The assistant carrier of nanoparticle is formed, taxol or its homologue are supported on above-mentioned carrier, wherein taxol or its homologue
Content be 4.5~20wt%, the size distribution of nanoparticle is in 50~250nm.
Preferably, the granularity of nanoparticle is concentrated mainly on 100~200nm.
Preferably, one or more of the poloxamer in PLURONICS F87 or poloxamer188.Zinc salt is nitric acid
Zinc or zinc chloride.The homologue of taxol is Docetaxel, Cephalomannine, baccatin III or 10- deacetylates bar Ka Ting
III。
Preferably, poloxamer and the weight ratio of taxol or its homologue are 1: 0.05~0.25.Poloxamer and zinc
The weight ratio of salt is 1: 0.0136~0.0567.
The preparation method of taxol and its homologue solid dispersions nanoparticle, using following steps:
(1) taxol or its homologue, poloxamer and zinc salt are mixed by formula, surpassed by solvent of absolute ethyl alcohol
Sound dissolves;
(2) above-mentioned solution is put into baking oven heating solvent flashing, is subsequently placed in refrigerator and is freezed;
(3) add water for injection in the colloidal state object obtained to step (2) and carry out ultrasonic disperse, nanometer is obtained after filtering
Grain.
Preferably, oven temperature control is at 100~120 DEG C, and heating evaporation absolute ethyl alcohol, more important is cause Pu Langni
Gram melt at high temperature, with the volatilization of ethanol, hydrophobic drug is wrapped in the hydrophobic region of pluronic, while metallic zinc from
Son can be coordinated with pluronic hydrophilic area PEO sections, assist the formation of nano particle.
Preferably, for refrigerator freezing temperature below 0 DEG C, more preferred temperature is -20 DEG C, under cooling conditions, Pu Lang
Ni Ke is separated out with the solid discrete form of packaging medicine, and the presence of zinc ion, which has to be formed beneficial to medicine solid dispersion, potentially to be received
Rice grain.
Solvent flashing simultaneously, taxol is obtained under zinc ion inducing action and its homologue is scattered in high temperature oven
Poloxamer hydrophobic region, after chilled, this inducing action is more notable, and at room temperature plus water ultrasonic disperse filters and produces Japanese yew
The nanoparticle of alcohol or its homologue solid dispersions.
Step (3) uses aperture to be filtered for 0.22 μm of filter membrane to the colloidal state object after disperseing, and not only acts as control
The size of nanoparticle processed, and play a part of aseptic filtration.
The nanoparticle being prepared can not only prepare injection as the intermediate of preparation can also prepare oral formulations.
Compared with prior art, the method for the nanoparticle that the present invention prepares paclitaxel solid dispersion is simple, novel, and not
Use the materials such as the polyethylene glycol described in prior art.But by the amphipathic and zinc ion by F68 with
The coordination cross-linked effect of PEO sections forms nano particle, and available for injection or oral, anticancer effect is good, is used in preparation process
High temperature be not only advantageous for the volatilization of ethanol, more important is causing pluronic to melt at high temperature, with waving for ethanol
Hair, hydrophobic drug is wrapped in the hydrophobic region of pluronic, while metal zinc ion can enter with pluronic hydrophilic area PEO sections
Row coordination, the formation of nano particle is assisted, then under cooling conditions, pluronic is analysed with the solid discrete form of packaging medicine
Go out, the presence of zinc ion has forms potential nano particle beneficial to medicine solid dispersion, after adding moisture to dissipate, is pre-formed potential
Nano particle can form the nanoparticle of high degree of dispersion under the driving of water.Be used to inject after the sterilizing of 0.22 μm of filtering with microporous membrane or
Orally.
Brief description of the drawings
Fig. 1 is the outward appearance picture of the nanoparticle for the paclitaxel solid dispersion that embodiment 1 is prepared;
Fig. 2 is the scanning electron microscope (SEM) photograph after the nanoparticle centrifugation for the paclitaxel solid dispersion that embodiment 1 is prepared freezes
Piece;
Fig. 3 is the grain size distribution of the nanoparticle for the paclitaxel solid dispersion that embodiment 1 is prepared;
Fig. 4 is that the nanoparticle for the paclitaxel solid dispersion that embodiment is prepared (contains in 10mM phosphate buffer solutions
0.1% Tween-80) in Cumulative release profile;
Fig. 5 is the X ray electronics after the nano particle centrifugation for the paclitaxel solid dispersion that embodiment 1 is prepared freezes
Power spectrum;
Fig. 6 is the lyophilized rear and its Related product of nanoparticle centrifugation for the paclitaxel solid dispersion that embodiment 1 is prepared
Wide-angle XRD;
Fig. 7 is tumor-bearing mice each group implanted solid tumor growth situation in embodiment 14.
Embodiment
The present invention is described in detail with specific embodiment below in conjunction with the accompanying drawings.
Embodiment 1
Take 25mg taxols and 100mg poloxamer188 3.0ml absolute ethyl alcohols to dissolve, add 30 μ l 1mol/L nitric acid
The ethanol solution ultrasound of zinc makes dissolving.120 DEG C of baking oven heating 1.5h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take out
Water for injection ultrasound is added to produce the nanoparticle of paclitaxel solid dispersion, (0.22 μm) filtering of miillpore filter.As a result obtain
Milky homogeneous colloids solution.
The nanoparticle of paclitaxel solid dispersion is finally obtained, its exterior appearance is subsphaeroidal, and particle diameter is 90-280nm (figures
1);Outward appearance photo (Fig. 2) is shown as the uniform turbid of milk shape;The average grain diameter that dynamic light scattering measures nanoparticle is 190nm
(Fig. 3);Extracorporeal releasing experiment (Fig. 4) display has sustained release behavior, is come out in 24h more than 90% insoluble drug release.Obtain taxol
Solid dispersions carry out XPS (Fig. 5) signs and show that zinc ion therein is in co-ordination state;Paclitaxel solid dispersion is obtained to enter
Diffraction maximum of row XRD signs (Fig. 6) display without other compositions, and taxol, P407, ZnCl2Itself feature is respectively provided with to spread out
Peak is penetrated, illustrates taxol in the nanoparticle, P407, ZnCl2It is not to exist with crystal form, but is deposited in the form of unformed
, this be more beneficial for medicine release and play drug effect.
Embodiment 2
Take 5mg taxols and 100mg poloxamer188 0.5ml absolute ethyl alcohols to dissolve, add 10 μ l 1mol/L nitric acid
The ethanol solution ultrasound of zinc makes dissolving.120 DEG C of baking oven heating 1.0h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take out
Water for injection ultrasound is added to produce the nanoparticle of paclitaxel solid dispersion, (0.22 μm) filtering of miillpore filter.As a result obtain
Light blue white uniformity colloidal solution.
Embodiment 3
Take 25mg taxols and 100mg PLURONICS F87 3.0ml absolute ethyl alcohols to dissolve, add 30 μ l 1mol/L nitric acid
The ethanol solution ultrasound of zinc makes dissolving.100 DEG C of baking oven heating 1.5h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take out
Water for injection ultrasound is added to produce the nanoparticle of paclitaxel solid dispersion, (0.22 μm) filtering of miillpore filter.As a result obtain
Milky homogeneous colloids solution.
Embodiment 4
Take 5mg taxols and 100mg PLURONICS F87 0.5ml absolute ethyl alcohols to dissolve, add 10 μ l 1mol/L nitric acid
The ethanol solution ultrasound of zinc makes dissolving.100 DEG C of baking oven heating 1h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take out and add
Water for injection ultrasound produces the nanoparticle of paclitaxel solid dispersion, (0.22 μm) filtering of miillpore filter.As a result obtain shallow
Blue and white homogeneous colloids solution.
Embodiment 5
Take 25mg taxols and 100mg poloxamer188 3.0ml absolute ethyl alcohols to dissolve, add 30 μ l 1mol/L chlorinations
The ethanol solution ultrasound of zinc makes dissolving.120 DEG C of baking oven heating 1.5h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take out
Water for injection ultrasound is added to produce the nanoparticle of paclitaxel solid dispersion, (0.22 μm) filtering of miillpore filter.As a result obtain
Milky homogeneous colloids solution.
Embodiment 6
Take 5mg taxols and 100mg poloxamer188 0.5ml absolute ethyl alcohols to dissolve, add 10 μ l 1mol/L chlorinations
The ethanol solution ultrasound of zinc makes dissolving.120 DEG C of baking oven heating 1h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take out and add
Water for injection ultrasound produces the nanoparticle of paclitaxel solid dispersion, (0.22 μm) filtering of miillpore filter.As a result obtain shallow
Blue and white homogeneous colloids solution.
Embodiment 7
Take 25mg taxols and 100mg PLURONICS F87 3.0ml absolute ethyl alcohols to dissolve, add 30 μ l 1mol/L chlorinations
The ethanol solution ultrasound of zinc makes dissolving.100 DEG C of baking oven heating 1.5h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take out
Water for injection ultrasound is added to produce the nanoparticle of paclitaxel solid dispersion, (0.22 μm) filtering of miillpore filter.As a result obtain
Milky homogeneous colloids solution.
Embodiment 8
Take 5mg taxols and 100mg PLURONICS F87 0.5ml absolute ethyl alcohols to dissolve, add 10 μ l 1mol/L chlorinations
The ethanol solution ultrasound of zinc makes dissolving.100 DEG C of baking oven heating 1h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take out and add
Water for injection ultrasound produces the nanoparticle of paclitaxel solid dispersion, (0.22 μm) filtering of miillpore filter.As a result obtain shallow
Blue and white homogeneous colloids solution.
Embodiment 9
Take 25mg Docetaxels and 100mg poloxamer188 3.0ml absolute ethyl alcohols to dissolve, add 30 μ l 1mol/L
The ethanol solution ultrasound of zinc chloride makes dissolving.120 DEG C of baking oven heating 1.5h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.
Take out the nanoparticle for adding water for injection ultrasound to produce Taxotere alcohol solid dispersoid, (0.22 μm) filtering of miillpore filter.
As a result milky homogeneous colloids solution is obtained.
Embodiment 10
Take 5mg Docetaxels and 100mg poloxamer188 0.5ml absolute ethyl alcohols to dissolve, add 10 μ l 1mol/L
The ethanol solution ultrasound of zinc chloride makes dissolving.120 DEG C of baking oven heating 1h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take
Go out the nanoparticle for adding water for injection ultrasound to produce Taxotere alcohol solid dispersoid, (0.22 μm) filtering of miillpore filter.Knot
Fruit obtains light blue white uniformity colloidal solution.
Embodiment 11
Take 25mg Docetaxels and 100mg PLURONICS F87 3.0ml absolute ethyl alcohols to dissolve, add 30 μ l 1mol/L
The ethanol solution ultrasound of zinc chloride makes dissolving.100 DEG C of baking oven heating 1.5h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.
Take out the nanoparticle for adding water for injection ultrasound to produce Taxotere alcohol solid dispersoid, (0.22 μm) filtering of miillpore filter.
As a result milky homogeneous colloids solution is obtained.
Embodiment 12
Take 5mg Docetaxels and 100mg PLURONICS F87 0.5ml absolute ethyl alcohols to dissolve, add 10 μ l 1mol/L
The ethanol solution ultrasound of zinc chloride makes dissolving.100 DEG C of baking oven heating 1h solvent flashings are put, are put more than -20 DEG C of refrigerator freezing 2h.Take
Go out the nanoparticle for adding water for injection ultrasound to produce Taxotere alcohol solid dispersoid, (0.22 μm) filtering of miillpore filter.Knot
Fruit obtains light blue white uniformity colloidal solution.
Embodiment 13 (inhibiting tumor assay, the sample of above-described embodiment 1)
1. experimental animal:SPF level Healthy females Kun Ming mice 96,18~22g of body weight, drinking-water of freely ingesting, 12h
Circulation light shines, and adapts to environment one week;Mouse cervix JEG-3 U14, the storage of pharmacology teaching and research room of Shenyang Pharmaceutical University.
2. the preparation of bearing mouse model:Extract the U14 of the good Kunming mouse interior generation (the 8th day) of growth conditions
Tumour cell (ascites), is diluted with sterile saline, and adjustment cell density is about 2.37 × 107ml-1, every mouse right fore
Inject 0.2ml in oxter.Aforesaid operations are aseptically carried out.
2. packet and administration:For mouse in connecing knurl the 5th day, gross tumor volume is all higher than 100mm3Afterwards, by gross tumor volume equilibrium with
Machine is divided into 7 groups, i.e. model control group;The commercially available taxol 10mg/kg groups of positive drug;Paclitaxel nano preparation gastric infusion 40mg/
Kg, 20mg/kg, 10mg/kg group;The number of animals of above each group is 12.Paclitaxel nano preparation tail vein administration 10mg/kg,
5mg/kg groups;Wherein 10mg/kg groups number of animals is 21, and 5mg/kg groups number of animals is 15.Paclitaxel nano preparation gavage is given
Gastric infusion is once every other day for each dosage group of medicine;The commercially available taxol 10mg/kg groups of positive drug and paclitaxel nano preparation tail vein are given
The every three days tail vein injections of each dosage group of medicine are administered once;The every three days tail veins of model control group give isometric physiology salt
Water, successive administration 10 days.
3. interpretation of result:Put to death within 10 days after animal is administered in first time, peel off tumor tissue, claim knurl weight, calculate tumour growth
Inhibiting rate (TIR), calculation formula is as follows:TIR=100% × (the average knurl weight of the average knurl weight-experimental group of control group)/control group is put down
Equal knurl weight.Average more than the knurl weight 1g of model control group, and at least 20% knurl weight can carry out interpretation of result in more than 400mg.Lotus
Knurl mouse each group implanted solid tumor growth situation is as shown in Figure 7.
The paclitaxel nano preparation of table 1 increases on U14 tumor-bearing mices body weight and tumour influences (n=10-12)
This test result indicates that, paclitaxel nano preparation each group shows good tumor killing effect.Gavage group and tail
The highest tumour inhibiting rate of vein group is respectively 68.89% and 70.26%, and the wherein highest tumour inhibiting rate of tail vein group is close to positive drug city
Sell the tumour inhibiting rate (71.21%) of taxol 10mg/kg groups.Self-control is oral, injection and commercially available injection do not have conspicuousness corvee.
Claims (4)
1. taxol and its homologue solid dispersions nanoparticle, it is characterised in that the nanoparticle using poloxamer as carrier, with
Taxol or its homologue are supported on above-mentioned carrier as the assistant carrier for forming nanoparticle by zinc salt, wherein taxol or
The content of its homologue is 4.5~20wt%, and the size distribution of nanoparticle is in 50~250nm;
Described poloxamer and the weight ratio of zinc salt are 1: 0.0136~0.0567;
Described zinc salt is zinc nitrate or zinc chloride;
The homologue of taxol is Docetaxel, Cephalomannine, baccatin III or 10- deacetylate baccatin IIIs;
Described poloxamer is 1: 0.05~0.25 with the weight ratio of taxol or its homologue;
Taxol and its homologue solid dispersions nanoparticle are prepared using following methods:
(1) taxol or its homologue, poloxamer and zinc salt are mixed by formula, it is molten to carry out ultrasound using absolute ethyl alcohol as solvent
Solution;
(2) above-mentioned solution is put into 120 DEG C of baking ovens and is heated to solvent flashing, be subsequently placed in -20 DEG C of refrigerators and freezed;
(3) add water for injection in the colloidal state object obtained to step (2) and carry out ultrasonic disperse, nanoparticle is obtained after filtering.
2. taxol according to claim 1 and its homologue solid dispersions nanoparticle, it is characterised in that described pool
Luo Shamu is selected from PLURONICS F87 or poloxamer188.
3. the preparation method of the taxol and its homologue solid dispersions nanoparticle as any one of claim 1-2,
Characterized in that, this method uses following steps:
(1) taxol or its homologue, poloxamer and zinc salt are mixed by formula, it is molten to carry out ultrasound using absolute ethyl alcohol as solvent
Solution;
(2) above-mentioned solution is put into 120 DEG C of baking ovens and is heated to solvent flashing, be subsequently placed in -20 DEG C of refrigerators and freezed;
(3) add water for injection in the colloidal state object obtained to step (2) and carry out ultrasonic disperse, nanoparticle is obtained after filtering.
4. the preparation method of taxol according to claim 3 and its homologue solid dispersions nanoparticle, its feature exist
In step (3) uses aperture to be filtered for 0.22 μm of filter membrane to the colloidal state object after disperseing.
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