CN102614110A - Stable polyethylene glycol medicinal micelle composition and preparation method thereof - Google Patents
Stable polyethylene glycol medicinal micelle composition and preparation method thereof Download PDFInfo
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- CN102614110A CN102614110A CN2012101283920A CN201210128392A CN102614110A CN 102614110 A CN102614110 A CN 102614110A CN 2012101283920 A CN2012101283920 A CN 2012101283920A CN 201210128392 A CN201210128392 A CN 201210128392A CN 102614110 A CN102614110 A CN 102614110A
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- paclitaxel
- micelle
- micelle composition
- polyethylene glycol
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Abstract
The invention relates to a stable polyethylene glycol medicinal micelle composition and a preparation method thereof. The micelle composition disclosed by the invention consists of pegylation taxol and taxol. The preparation method comprises the following steps of: preparing pegylation taxol by taking hydrophilic polyethylene glycol, taxol and a small molecular connecting agent as starting raw materials; and wrapping free taxol in the kernel of a micelle by taking the pegylation taxol as a micelle carrier material to form the micelle composition. The particle diameter of the micelle composition prepared with the method is about 100 nanometers. As proved by experiments, the micelle composition has a good stabilizing effect on taxol, and can be used for remarkably enhancing the antitumor curative effect of taxol.
Description
Technical field
The present invention relates to micelle composition of a kind of hydrophobic drug and its hydrophilic polymer derivant formation and preparation method thereof, being specifically related to the Pegylation paclitaxel is the micelle composition that the micelle carrier material prepares paclitaxel, belongs to field of pharmaceutical preparations.
Background technology:
Paclitaxel is from taxus Pacific yew tree, to separate the natural Diterpenes material that obtains, and its molecular formula is C47H51NO14, and molecular weight is 853.9.Paclitaxel is present widely used a kind of natural anti-cancer drugs, and its mechanism of action mainly is to combine with free microtubule time body, and constantly promotes microtubule polymerization, and then disturbs the carrying out of mitosis and cellular replication; Paclitaxel injection
was PTS in 1992 through the approval of united states drug food control office; Be used to treat multiple cancers such as ovarian cancer, breast carcinoma, skin carcinoma, pulmonary carcinoma, have very obvious treatment effect.
Paclitaxel, fat-soluble strong, be soluble in organic solvents such as chloroform, ethanol; Be insoluble in water; Its dissolubility is less than 0.004g/L; In order to improve the dissolubility of paclitaxel in aqueous solution,
used Cremophor EL (condensation product of polyethoxy Oleum Ricini and oxirane) and come the solubilising paclitaxel with 1: 1 mixed liquor of dehydrated alcohol.Cremophor EL has been proved to be big toxic and side effects; After giving the Canis familiaris L. intravenously administrable, can produce vasodilation, dyspnea, lethargy, hypotension and death; And this solvent has the high sensitization of blood vessel; Before the clinical use, need carry out pretreatment, make paclitaxel injection application clinically receive a lot of restrictions through antihistaminic.
The method that increases taxol soluble at present mainly contains two types, and one type is to utilize the hydroxyl of paclitaxel parent nucleus C2 ' position, C7 position to introduce water soluble group, obtains water soluble taxad alcohol derivative; Another kind of is through preparing the microparticle formulation of paclitaxel, like Emulsion, liposome and micelle etc.Chinese patent (publication number CN1895676) is carrier with the Polyethylene Glycol, and hydroxyacetic acid or lactic acid are compared with paclitaxel as the taxanes water-soluble prodrug of linking arm, and water solublity and tumour inhibiting rate obviously strengthen.Chinese patent 00109748.2 utilizes aminoacid or oligopeptide to get up to constitute taxol soluble derivative to water miscible Polyethylene Glycol and paclitaxel chemical combination bonding.Though these hydrophilic derivatives can both increase the water solublity of paclitaxel to a certain extent; But these hydrophilic polymer method of modifying have a common weak point; The PEG carrier is very limited to the drug loading of drug molecule, and generally each bar PEG chain can only connect a paclitaxel molecule.In recent years, be that the micelle delivery system that carrier material prepares insoluble drug is used widely with amphipathic altogether block polymer.In Korea S's listing, this product is the micelle carrier material with diblock polymer polyethylene glycol-lactic acid to the micellization paclitaxel Genexol-PM of Korea S Samyang company development.Someone adopts diblock polymer polyethylene glycol-lactic acid to prepare paclitaxel micelle carrier system, and the test of paclitaxel Isotopic Distribution shows that after this micelle got in the body, micelle disintegrated rapidly, discharges medicine.(Zhang?X.，et?al.，Anti-tumor?efficacy?and?biodistribution?of?intravenous?polymeric?micellar?paclitaxel.Anticancer?Drugs，1997，8(7)：696-701；Kim?S.C.，et?al.，In?vivo?evaluation?of?polymeric?micellar?paclitaxel?formulation：toxicity?and?efficacy.J?Control?Release，2001，72(1-3)：191-202)。In addition; It is the taxone micelle of carrier material with diblock polymer methoxy poly (ethylene glycol)-polycaprolactone that Chinese patent (publication number 102198083) discloses a kind of, and drug loading can reach 5-16%, compares with the commercial preparation; Eliminate comparatively fast, can reduce the toxicity of paclitaxel blood vessel.With the diblock polymer is the toxicity that the paclitaxel micelle can significantly reduce
of preparing carriers, but readily degradable problem in this external physical stability problem of based fine particles administration ubiquity and the body.
Summary of the invention
The purpose of this invention is to provide micelle composition that a kind of stable hydrophobic drug and its polyethyleneglycol derivative form and preparation method thereof, overcome in the prior art such as surfactant toxicity, drug loading is low and physical stability problem.
The present invention realizes above-mentioned purpose through following technical scheme:
The present invention provides a kind of Pegylation paclitaxel type micelle composition, and this micelle composition is the micelle carrier material with the Pegylation paclitaxel, and free paclitaxel is encapsulated in has in the micellar kernel of nucleocapsid structure;
Wherein said Pegylation paclitaxel be Polyethylene Glycol to pass through a end that the hydroxyl covalent bond of micromolecule linking arm and paclitaxel C2 ' position or C7 position forms be that hydrophobic structure, the other end are hydrophilic structure and middlely are the amphipathic derivatives of micromolecule linking arm, but its structural representation simple table is shown:
PEG-Linker-PTX
Wherein, PEG is a Polyethylene Glycol; Linker is the micromolecule linking arm, and its molecular weight is 20～500 dalton; PTX is a paclitaxel.
Wherein micromolecular compound is as linking arm, and its two end combines with hydrophilic polyglycol and paclitaxel through covalent bond respectively.The molecular weight of micromolecule linking arm is 20～500 dalton.The micromolecule linking arm is selected from: aliphatic dibasic acid, hydroxyl lactic acid, lactic acid, oligopeptide and dihydroxylic alcohols.The micromolecule linking arm is preferably succinic acid.
Pegylation paclitaxel type micelle composition provided by the invention, paclitaxel accounts for 0.5～30% of micelle composition gross weight, and the Pegylation paclitaxel accounts for 70～99.5% of micelle composition gross weight.
The size of Pegylation paclitaxel type micelle composition provided by the invention is 30～300nm.
Used Polyethylene Glycol is that the hydroxyl Polyethylene Glycol in two ends or single-ended is the Polyethylene Glycol of hydroxyl among the present invention.
The present invention provides a kind of Pegylation paclitaxel type micelle composition, and the weight average molecular weight of wherein said Polyethylene Glycol is preferably 800～20000 dalton.
The method for preparing of Pegylation paclitaxel type micelle composition is to be initiation material with hydrophilic material Polyethylene Glycol, paclitaxel and micromolecular compound among the present invention; Prepare hydrophobic drug Pegylation paclitaxel earlier; Be the micelle carrier material with the Pegylation paclitaxel then, be prepared into the micelle composition that the micelle kernel is encapsulated with free hydrophobic drug through the solvent evaporation membrane process.
Pegylation paclitaxel type micelle composition of the present invention can exist with the aqueous dispersions form; Also can be according to product needed; Be prepared into the pharmaceutical dosage forms that is fit to preservation and uses, carry out cryodesiccated dried frozen aquatic products dosage form like the liquid preparation form or to aqueous dispersions.
Pegylation paclitaxel type micelle composition of the present invention has the following advantages:
1, the present invention selects polyethyleneglycol modified insoluble drug paclitaxel for use; Form micelle with this amphipathic derivatives in the aqueous solution self assembly then; Wrap up insoluble drug simultaneously; Need not to use surfactant-based solubilizing agents such as polyoxyethylene castor oil, eliminated by traditional solvent bring such as hidden danger such as anaphylaxis, improved the safety of medicine greatly.
2, the micelle composition drug loading for preparing among the present invention is high, the particle size distribution homogeneous, and vitro stability is good.
3, micelle composition of the present invention shows through animal vivo test, can obviously improve the antitumor curative effect of paclitaxel, has good clinical value.
Description of drawings:
The MALDI-TOF mass spectrum of synthetic Pegylation paclitaxel among Fig. 1 embodiment 1
The Pegylation paclitaxel type MICELLAR STRUCTURE sketch map of Fig. 2 embodiment 4 preparations
Fig. 3 has shown the particle size distribution figure and the Electronic Speculum figure of the Pegylation paclitaxel type micelle composition that laser particle analyzer is measured.A: particle size distribution; B: transmission electron microscope picture
Fig. 4 is micelle composition of the present invention and PEG-PLA micelle medicine crystallize figure
The haemolysis result of Fig. 5 PEG-PTX/PTX micelle and commercial preparation Taxol
Fig. 6 is micelle composition of the present invention and the comparative study of the micellar antitumor of paclitaxel PEG-PLA drug effect.A: tumor size figure; B: tumor growth curve; C: nude mice body weight change curve after the administration;
The specific embodiment
Below further specify and explain the present invention through embodiment, but the restriction of not carrying out as the present invention.
Synthesizing of embodiment 1, Pegylation paclitaxel
With MPEG
5000(20g 4mmol) is added in the 100mL toluene, reflux water-dividing, and pressure reducing and steaming toluene adds CHCl then
3(100mL), and succinic anhydride (2.00g, 20mmol) and pyridine (1mL), backflow 48h, pressure reducing and steaming CHCl
3, adding distilled water, sucking filtration is removed the solid of generation, will filtrate with CHCl
3Extraction (100mL * 3) merges CHCl
3Layer, saturated common salt washing, anhydrous sodium sulfate drying filters, and is concentrated into about 30mL, and add a large amount of ether and make and separate out solid, sucking filtration, oven dry, getting product is white solid.
(560mg 0.11mmol) divides water 1h with refluxing toluene, and pressure reducing and steaming toluene then is with CH with the MPEG-succinic acid
2Cl
2(5mL) dissolving, and adding 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCHCl) under 0 ℃ (38mg, 0.20mmol); Behind the reaction 20min, and adding PTX (86mg, 0.10mmol); N, (33 μ L are 0.20mmol) with 4-dimethylamino naphthyridine (DMAP) (1.2mg for N-diisopropylethylamine (DIEA); 0.01mmol), rise to room temperature naturally, reaction 24h.After crossing the post separation, with CH
2Cl
2Dissolving, the saturated common salt washing is filtered, and is concentrated into dried.Mass Spectrometer Method, result such as Fig. 1 show that paclitaxel is connected on the Polyethylene Glycol.
Synthesizing of embodiment 2, Pegylation paclitaxel
Synthetic method wherein replaces succinic anhydride with suberic acid with embodiment 1, and obtaining with the suberic acid is the paclitaxel Polyethylene Glycol of linking arm.
Synthesizing of embodiment 3, Pegylation paclitaxel
Synthetic method is with embodiment 1, wherein with MPEG
2000Replace MPEG
5000, obtain the paclitaxel polyethyleneglycol derivative of different molecular weight.
The preparation and the sign of embodiment 4, Pegylation paclitaxel type micelle composition
Adopt solvent evaporation thin film aquation legal system to be equipped with micelle.Take by weighing that synthetic 10mg PEG-PTX and 1mg PTX place the 25ml eggplant-shape bottle among the embodiment 1; Add the dissolving of 3ml acetonitrile; Evaporate to dryness is rotated in decompression in 37 ℃ of water-baths then; Treat that organic solvent volatilizes the back and adds 2mlPBS solution vortex aquation, aquation back fully is ultrasonic to the solution clarification in 60 ℃ of water-baths, promptly gets Pegylation paclitaxel type micelle composition (PEG-PTX/PTX micelle).MICELLAR STRUCTURE sketch map such as Fig. 2 of preparation.(Dynamic Light Scattering DLS) measures its granularity and distribution to utilize dynamic light scattering; Utilize the form of transmission electron microscopy polymer micelle.Its micelle character is seen table 1 and Fig. 3.
The preparation and the sign of embodiment 5, Pegylation paclitaxel type micelle composition
Take by weighing the PEG-PTX of 20mg respectively and the PTX of 1mg prepares Pegylation paclitaxel type micelle composition according to the method for preparing of embodiment 4.Particle size distribution result sees table 1.
| PEG-PTX∶PTX | Particle diameter | PDI |
| 10∶1 | 110.2nm±5.3 | 0.201±0.016 |
| 20∶1 | 102.5nm±4.6 | 0.194±0.023 |
Embodiment 6 study on the stability
Get the PEG-PTX/PTX micelle and the PEG-PLA/PTX micelle of preparation, under the room temperature equivalent environment, observe preparation and change and use the photo record, and take a morsel respectively at 0h, 2h, 4h, 8h and to use microscopic examination, the result sees Fig. 4.The result shows in the PEG-PLA/PTX group and begins just to have the paclitaxel needle to occur at 2h, is that the micelle stability of carrier obviously is better than the PEG-PLA/PTX micelle with the polyethyleneglycol derivative of paclitaxel.
Embodiment 7 hemolytics are investigated
Get PEG-PTX/PTX micelle and each 2.5ml of commercial preparation Taxol, place test tube, as sample cell.Other gets water recently distilled 5ml as the positive control pipe, with 0.9% sodium chloride solution 5ml as the negative control pipe.Above-mentioned each pipe adds 2% red blood cell suspension 2.5ml, mixing respectively.37 ℃ of water bath heat preservation 30min take out, and put centrifugal 5min (5000rpm) in the centrifuge then; Drawing supernatant moves in the cuvette; With 0.9% sodium chloride solution is blank, measures each trap concerning solution in the 570nm wavelength respectively, and calculates the haemolysis degree of each formulation samples according to following formula:
Haemolysis degree %=(A appearance-A is cloudy)/(A sun-A is cloudy) * 100%
The result sees Fig. 5, and the result shows, is that the micelle of carrier does not have hemolytic basically with the Pegylation paclitaxel, obviously is better than the commercial preparation.
Embodiment 8 anti-tumor activity tests
Female BALB/c nude mice (18-22g, Beijing dimension tonneau China laboratory animal), the axil subcutaneous vaccination 4 * 10 in the right side
6Individual inoculation MCF-7 cell; Gave PEG-PTX/PTX micelle and PEG-PLA/PTX micelle in the 10th day, 12 days, 14 days, 16 days and 18 days with the inoculation back respectively, dosage is mg/kg, the body weight of measuring nude mice in second day after each administration; And sign and the behavioral activity of observation nude mice; And use vernier caliper measurement respectively to organize the line of apsides of tumor, and calculate gross tumor volume V (V=[Length * (Width) 2]/2), draw gross tumor volume-time variation diagram.Put to death animal in the 18th day behind tumor inoculation, and peeled off tumor, the weighing tumor is heavy, and tumor is carried out film recording.
The result sees Fig. 6, and the micellar anti-tumor activity of PEG-PTX/PTX that shows same dose is apparently higher than the PEG-PLA/PTX micelle, and the weight of animals changes similar basically with PEG-PLA/PTX, there was no significant difference.
Embodiment 9,
In the micelle composition, paclitaxel accounts for 0.5% of micelle composition gross weight, and the Pegylation paclitaxel accounts for 99.5% of micelle composition gross weight.
Take by weighing that synthetic PEG-PTX and PTX place eggplant-shape bottle among the embodiment 1; Add the acetonitrile dissolving; Evaporate to dryness is rotated in decompression in 37 ℃ of water-baths then; Treat that organic solvent volatilizes the back and adds PBS solution vortex aquation, aquation back fully is ultrasonic to the solution clarification in 60 ℃ of water-baths, promptly gets Pegylation paclitaxel type micelle composition.
Embodiment 10,
In the micelle composition, paclitaxel accounts for 30% of micelle composition gross weight, and the Pegylation paclitaxel accounts for 70% of micelle composition gross weight.
Take by weighing that synthetic PEG-PTX and PTX place eggplant-shape bottle among the embodiment 1; Add the acetonitrile dissolving; Evaporate to dryness is rotated in decompression in 37 ℃ of water-baths then; Treat that organic solvent volatilizes the back and adds PBS solution vortex aquation, aquation back fully is ultrasonic to the solution clarification in 60 ℃ of water-baths, promptly gets Pegylation paclitaxel type micelle composition.
Claims (10)
1. the micelle composition that forms of Pegylation paclitaxel and paclitaxel is characterized in that this micelle composition is the micelle carrier material with the Pegylation paclitaxel, and free paclitaxel is encapsulated in this micellar kernel.
2. micelle composition as claimed in claim 1; Wherein said Pegylation paclitaxel be Polyethylene Glycol to pass through a end that the hydroxyl covalent bond of micromolecule linking arm and paclitaxel C2 ' position or C7 position forms be that hydrophobic structure, the other end are hydrophilic structure and middlely are the amphipathic derivatives of micromolecule linking arm, its structural representation is expressed as:
PEG-Linker-PTX
Wherein, PEG is a Polyethylene Glycol; Linker is the micromolecule linking arm, and its molecular weight is 20～500 dalton; PTX is a paclitaxel.
3. like claim 1 described micelle composition, it is characterized in that the said micromolecule linking arm that is used to connect paclitaxel and Polyethylene Glycol is selected from: aliphatic dibasic acid, hydroxyl lactic acid, lactic acid, oligopeptide and dihydroxylic alcohols.
4. like claim 2 described micelle compositions, it is characterized in that said micromolecule linking arm is a succinic acid.
5. like claim 1 described micelle composition, it is characterized in that in the said micelle composition, paclitaxel accounts for 0.5～30% of micelle composition gross weight, the Pegylation paclitaxel accounts for 70～99.5% of micelle composition gross weight.
6. like claim 1 described micelle composition, it is characterized in that the size of said micelle composition is 30～300nm.
7. like claim 1 described micelle composition, it is characterized in that said Polyethylene Glycol is that the hydroxyl Polyethylene Glycol in two ends or single-ended is the Polyethylene Glycol of hydroxyl.
8. like claim 1 described micelle composition, it is characterized in that the mean molecule quantity of said Polyethylene Glycol is 800～20000 dalton.
9. like the method for preparing of claim 1 described micelle composition; It is characterized in that; With hydrophilic material Polyethylene Glycol, paclitaxel and micromolecular compound is initiation material; Preparation Pegylation paclitaxel is the micelle carrier material with the Pegylation paclitaxel then earlier, is prepared into the micelle composition that the micelle kernel is encapsulated with paclitaxel through conventional method.
10. like claim 1 or 8 described micelle compositions, it is characterized in that said micelle composition can the aqueous dispersions form exist, and also can carry out drying to aqueous dispersions according to product needed, exists with solid form.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432591A (en) * | 2013-08-19 | 2013-12-11 | 中国科学院长春应用化学研究所 | Nano-micelle medicine using ethylene epoxide polymer as a carrier and a preparation method thereof |
| CN104274401A (en) * | 2014-07-25 | 2015-01-14 | 中国医学科学院药用植物研究所 | High drug-loading content nano suspension for camptothecin medicine based on HCPT-PEG (hydroxycamptothecin-polyethylene glycol) and preparation method of high drug-loading content nano suspension |
| CN104548125A (en) * | 2014-12-30 | 2015-04-29 | 北京大学 | Preparation and application of PEG-PTX-NCs (pegylation-paclitaxel-nanocrystals) |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432591A (en) * | 2013-08-19 | 2013-12-11 | 中国科学院长春应用化学研究所 | Nano-micelle medicine using ethylene epoxide polymer as a carrier and a preparation method thereof |
| CN103432591B (en) * | 2013-08-19 | 2015-04-08 | 中国科学院长春应用化学研究所 | Nano-micelle medicine using ethylene epoxide polymer as a carrier and a preparation method thereof |
| CN104274401A (en) * | 2014-07-25 | 2015-01-14 | 中国医学科学院药用植物研究所 | High drug-loading content nano suspension for camptothecin medicine based on HCPT-PEG (hydroxycamptothecin-polyethylene glycol) and preparation method of high drug-loading content nano suspension |
| CN104548125A (en) * | 2014-12-30 | 2015-04-29 | 北京大学 | Preparation and application of PEG-PTX-NCs (pegylation-paclitaxel-nanocrystals) |
| CN104548125B (en) * | 2014-12-30 | 2017-12-12 | 北京大学 | A kind of preparation and its application of Pegylation paclitaxel nano crystal |
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