CN103920163B - A kind of paclitaxel complex, preparation method and applications - Google Patents
A kind of paclitaxel complex, preparation method and applications Download PDFInfo
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- CN103920163B CN103920163B CN201410095972.3A CN201410095972A CN103920163B CN 103920163 B CN103920163 B CN 103920163B CN 201410095972 A CN201410095972 A CN 201410095972A CN 103920163 B CN103920163 B CN 103920163B
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- paclitaxel
- cyclodextrin
- acrylated
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- acrylic acid
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Abstract
The invention discloses a kind of paclitaxel complex, acrylated cyclodextrin modified acrylic acid polymer and the complex of paclitaxel.Complex cyclodextrin isIn one or more；The polyacrylic mass ratio that paclitaxel is modified with acrylated CD is 2:1 5.The molecular weight of described acrylated cyclodextrin modified acrylic acid polymer is 5000～50000, and wherein the molar ratio of cyclodextrin units and acrylic acid units is between 1:4 to 1:10.UtilizeAnd the acylation between acryloyl chloride, has first synthesized acrylatedThen directly it is prepared for by radical copolymerization method in aqueousThe polyacrylic acid (CDPAA) modified.The complex that CDPAA paclitaxel prepared by the present invention is formed, paclitaxel can be played solubilising, the dissolubility of paclitaxel can be brought up to 3.6mg/ml from from 0.25 ì g/ml, thus the clinical practice to anti-cancer medicine paclitaxel provides a kind of new feasible approach.
Description
Technical field:
The present invention relates to a kind of enhancing water miscible complex of anti-cancer medicine paclitaxel, prepare and apply.
Background technology:
Paclitaxel (Paclitaxel, PTX) is a kind of very effective antitumor drug, be mainly used in treat ovarian cancer and
Breast carcinoma.But its clinical value can not get a desired effect, it is primarily due to its dissolubility in water very
Difference.Meanwhile, PTX lacks can the functional group of ionizing, its dissolubility is affected little by solution ion strength or pH value,
Thereby ensure that under conditions of not losing its property of medicine, increase its dissolubility by functional group conversions, the clinic for paclitaxel should
With making great sense.Therefore, the lyotropy of PTX becomes a critically important problem.
Existing research display: PTX is loaded in the polymer micelle of some inner hydrophobic, the outside parent of these micelles
Water, thus can be stable in the presence of in aqueous solution, is thus equivalent to add the water solublity of PTX.Some solubilisings to PTX
Have the auxiliary agent such as N-picolylnicotinamide(PNA of remarkable result) etc. be also introduced into block macromolecular micelle, use
In strengthening PTX dissolubility in water.
Cyclodextrin (Cyclodextrin is called for short CD) is to be passed through by some glucose unitsGlycosidic bond combines and shape
The chiral ring oligosaccharide compound become.According to the number of construction unit, cyclodextrin can be divided into respectively by 6,7,8 glucoses
Unit composition(Fig. 5), their structure is all in round table-like, and inside is one and has certain size
Hydrophobic cavity, it is possible to inclusion hydrophobic guest molecules.Cyclodextrin and small molecule derivative thereof are receive much concern in recent years novel
Pharmaceutical pack condensation material, they can improve some character of medicine so that it is is prone to allotment and takes, and strengthens the stability of medicine,
Reduce the toxic and side effects of medicine, strengthen the bioavailability of medicine.
Cyclodextrin introducing some polymeric system and can retain its cavity and more hydroxyl, this is just polymerized for cyclodextrin
Thing is combined with the guest molecule such as Organic substance, inorganic matter and provides possibility.Thus be equivalent to combine polymeric material stick with paste with ring
The dual-use function of essence, even can produce some new performances, can prepare functional material as required.Such as that cyclodextrin is solid
Surely arrive cellulose surface, process accordingly, it is possible to prepare the various performances such as savory, drug effect, moisturizing, anticorrosion
Fibrous material.By poly-time, sub-ethamine-polyvinyl alcohol graft copolymerized on cyclodextrin, the macromole of preparation may be used for gene and medicine is defeated
Send.
Polyacrylic acid (polyacrylic acid, PAA) aqueous stability is fabulous, is difficult to corruption, has the most raw
The thing compatibility, has a wide range of applications at food, field of medicaments, as can be as gastric mucosa protectant etc..The invention provides
The polyacrylic acid composite using cyclo-dextrin-modified strengthens the deliquescent method of paclitaxel.
Summary of the invention:
It is an object of the invention to provide a kind of enhancing water miscible complex of anti-cancer medicine paclitaxel, preparation method and answer
With.Utilize the acylation between cyclodextrin and acryloyl chloride, first synthesize acrylated cyclodextrin.Then directly at aqueous solution
In be prepared for cyclodextrin modified polyacrylic acid by radical copolymerization method.The polyacrylic acid modified is multiple with paclitaxel
Closing, paclitaxel can be made to be dissolved in rapidly water, the dissolubility of paclitaxel brings up to 3.6mg/ml, solubilising 14400 from 0.25 ì g/ml
Times.
The complex of paclitaxel complex, acrylated cyclodextrin modified acrylic acid polymer and paclitaxel.
Described complex cyclodextrin is
In one or more.
The molecular weight of polymer is 5000～50000, and wherein the molar ratio of cyclodextrin units and acrylic acid units is at 1:4
Between 1:10.
The water miscible complex of enhancing anti-cancer medicine paclitaxel of the present invention, can by the dissolubility of paclitaxel from
0.25 ì g/ml brings up to 3.6mg/ml, solubilising 14400 times.
The preparation method of described paclitaxel complex, comprises the following steps:
1) acrylated(PACD) synthesis, weighs what recrystallization was crossedIt is dissolved in DMF, adds three
Ethamine is as positive reaction catalyst.In ice-water bath, under stirring, drip acryloyl chloride, be basically completed to reaction.By mixture mistake
Filter, purifies product PACD, the solid PACD of collection in filtrate with mixed solvent method and is placed in vacuum tank dry.
2)Modify the synthesis of polyacrylic acid (chain) CDPAA, weigh PACD and be dissolved in water, drip different amounts of respectively
Acrylic acid, causes polymerization under 70 DEG C of nitrogen protective conditions, reacts about 1-2 hour and complete.Solution obtains through dialysis, lyophilizationThe polyacrylic acid (CDPAA) modified.
3) paclitaxel is dissolved in a small amount of ethanol, paclitaxel ethanol solution is addedThe polyacrylic acid modified
(CDPAA), in aqueous solution, mixed solution is sealed and is stirred at room temperature.
4) evaporating ethanol solvent, sucking filtration removes the paclitaxel having neither part nor lot in inclusion, gained filtrate is spin-dried for, and vacuum is done
Dry, i.e. prepareThe polyacrylic acid CDPAA modified and paclitaxel complex.
The paclitaxel complex that above-mentioned preparation method obtains application in tumor.
Beneficial effects of the present invention: by being directly prepared for by radical copolymerization method in aqueousModify
Polyacrylic acid (CDPAA).Gained paclitaxel composite solids product proves through infrared spectrum, NMR (Nuclear Magnetic Resonance) spectrum etc..This
Bright cyclodextrin modified acrylic acid polymer is as a kind of low toxicity and pharmaceutical carrier soluble in water, to anti-cancer medicine paclitaxel
After carrying out inclusion, this medicine dissolubility in water is greatly improved, and can be improved from from 0.25 ì g/ml by the dissolubility of paclitaxel
To 3.6mg/ml.Thus solve anti-cancer medicine paclitaxel key issue in the application.CDPAA paclitaxel prepared by the present invention
The complex formed, thus the clinical practice to anti-cancer medicine paclitaxel provides a kind of new feasible approach.
Accompanying drawing illustrates:
Fig. 1The infrared spectrogram of PACD, CDPAA, PAA.
Fig. 2The nuclear magnetic spectrogram of PACD and CDPAA.
Fig. 3Modify the dissolubility picture of polyacrylic acid and paclitaxel complex.
Fig. 4Modify polyacrylic synthetic route chart.
Fig. 5Structural representation.
Detailed description of the invention:
Embodiment, it is as follows with the method for paclitaxel complex that the present invention prepares cyclodextrin modified polyacrylic acid:
1) acrylatedThe synthesis of the acrylated CD of-cyclodextrin
Weigh the CD that recrystallization crosses to be dissolved in the DMF of excess (more than five times of CD mass), transfer to, in three-necked bottle, add
Enter triethylamine (such as 0.5-2 times of CD mass) as positive reaction catalyst.Three-necked bottle is placed in ice-water bath, uses under the conditions of magnetic agitation
Dropping funnel dropping acryloyl chloride, under room temperature, continuation stir about half an hour, reaction is basically completed.Mixture is filtered, discards filter
Slag, filtrate is transferred in conical flask.By mixed solvent method (acetone methanol) purified product, (acetone is both poor solvent, first
Alcohol is two solvents of product, the poor solvent of raw material), add acetone precipitation and go out product cyclo-dextrin-modified acrylate monomer
And unreacted is complete (PACD)Filter, discard mother solution.Solids with methanol is partly dissolved, and filters, discards filtering residue.Filtrate is continued
Continuous acetone precipitation goes out solid, collects solid product PACD, so repeats 1～2 time, until filtrate through silver nitrate detection without chlorine from
Son.The solid PACD collected is placed in vacuum tank and is dried, temperature 30～40 DEG C.
CD is?.
2) acrylated CD modifies the synthesis of polyacrylic acid chain,
Weigh PACD to be dissolved in water, drip a certain amount of acrylic acid (AA) AA and be 0.5-2 times of PACD, make AA:CD's
Ratio is from 10:1 to 4:1, and oil bath is heated to 70 DEG C, adds a certain amount of potassium peroxydisulfate and cause polymerization under nitrogen protective condition,
Stop after reacting about 1.5 hours.Solution is transferred to dialyse in bag filter, and lyophilizing after the cooling of solution liquid nitrogen is collected, to be analyzed.System
The polyacrylic acid that the standby CD of going out modifies.
3) paclitaxel is dissolved in a small amount of ethanol, is then added to the polyacrylic acid aqueous solution that acrylated CD modifies
In, stirring, mixed solution is stirred at room temperature 12 hours.The polyacrylic mass ratio that paclitaxel is modified with acrylated CD
For 2:1-5.
4) removing alcohol solvent is evaporated under reduced pressure, and sucking filtration removes the paclitaxel having neither part nor lot in inclusion, gained filtrate is spin-dried for, vacuum
It is dried, i.e. prepares polyacrylic acid and paclitaxel complex that CD modifies.
Cyclodextrin modified acrylic acid polymer involved in the present invention and paclitaxel complex synthesize as follows, I
ChooseIllustrated for representative cyclodextrin:
1)Modify polyacrylic synthesis
Weigh what recrystallization was crossed8.0g is dissolved in 20ml DMF, transfers in 100ml three-necked bottle, adds 3ml tri-
Ethamine is as positive reaction catalyst.Three-necked bottle is placed in ice-water bath, drips 3ml acryloyl with Dropping funnel under the conditions of magnetic agitation
Chlorine, controls rate of addition at 1d/s～2d/3s.Dripping and finish, under room temperature (25～30 DEG C), continuation stir about half an hour, reacts the completeest
Become.Being filtered by mixture, discard filtering residue, filtrate is transferred in 150ml conical flask.By mixed solvent method purified product, (acetone is
Both poor solvents, methanol is two solvents of product, the poor solvent of raw material), add 100ml acetone precipitation and go out product PACD
Complete with unreactedFilter, discard mother solution.Solid 20ml methanol fractions dissolves, and filters, discards filtering residue.Filtrate is continued
Go out solid with 100ml acetone precipitation, collect solid product PACD, so repeat 1～2 time, until filtrate detects nothing through silver nitrate
Chloride ion.The solid PACD collected is placed in vacuum tank and is dried, temperature 30～40 DEG C.
Weigh 0.2g PACD to be dissolved in 20ml water, drip a certain amount of acrylic acid, make AA:Ratio from 10:1
To 4:1, oil bath is heated to 70 DEG C, adds a certain amount of potassium peroxydisulfate and cause polymerization under nitrogen protective condition, and reaction about 1.5 is little
Stop time after.Solution transfers to dialysis 48h in bag filter (molecular weight less than 3500 removal), changes water 3～4 times, and solution liquid nitrogen is cold
But lyophilizing after, collects, to be analyzed.PrepareThe polyacrylic acid modified.
2)The polyacrylic acid modified and the synthesis of paclitaxel complex
Paclitaxel is dissolved in a small amount of ethanol, joinsIn the polyacrylic acid aqueous solution modified, stirring, will be mixed
Close solution to seal and be stirred at room temperature.Evaporating ethanol solvent, sucking filtration removes the paclitaxel having neither part nor lot in inclusion, is filtered by gained
Liquid is spin-dried for, vacuum drying, i.e. preparesThe polyacrylic acid modified and paclitaxel complex.
3)The polyacrylic acid modified and the sign of paclitaxel complex
The polyacrylic acid modified characterizes by the following method:
Infrared spectrum (Bruker Vector22 infrared spectrometer)
PACD, CDPAA, polyacrylic acid (PAA) and raw materialInfrared spectrogram compare and see Fig. 1,At 1500cm-1-2000cm-1In the range of without obvious absworption peak, and PACD is at 1727cm-1And 1663cm-1There are two strong absworption peaks at place, respectively
Belong to the stretching vibration of C=O and C=C, illustrate that acryloyl group (CH2=CH-C (=O)-) is successfully received by acylationOn.Characteristic absorption peak be concentrated mainly on finger print region (pyranoid ring C-O stretching vibration 1035cm-1In), these are special
Levy peak can observe in PACD spectrogram, explanationThe most successfully it is linked on PACD, is prepared forModified
Acrylate monomer.And in CDPAA spectrogram, 1663cm-1Place belongs to the characteristic peak of C=C double bond, becomes very in CDPAA spectrogram
Weak, substantially can ignore.This is because C=C double bond take part in radical polymerization, becoming singly-bound, characteristic peak the most herein is not
Multiple existence.1418cm-1Double key carbon hydrogen bonds peak, place disappears the most substantially, and both confirm the double bond transformation to singly-bound simultaneously.This
Illustrate that PACD take part in radical polymerization well it was confirmed the acrylate polymer of cyclo-dextrin-modified is the most successfully prepared.
NMR (Nuclear Magnetic Resonance) spectrum (Bruker DRX500 nuclear magnetic resonance chemical analyser)
In order to further confirmThe polyacrylic structure modified, carries out HNMR analysis by product, and result is shown in figure
2。In construction unit, the chemical shift ownership of hydrogen atom is respectively as follows: These proton peak can be observed in the spectrogram of PACD and CDPAA.Relatively
PACD withSpectrogram, obvious change is that the former is manyThe proton peak at place, this is double bond proton peak,
I.e. proton peak in acryloyl group.The existence at this peak, explanationThe most acrylated.But this peak exists
CDPAA but disappears, double bond generation radical polymerization is described, becomes singly-bound, the substitute isAnd 2.1
Neighbouring alkyl proton peak.
Dissolubility
In terms of strengthening PTX dissolubility, there is considerable influence, therefore have studied in main polymer chain, different PTX
The content impact on PTX dissolubility.Fig. 3 is differentPTX dissolubility picture under ratio.From the figure, it can be seen that PTX
Dissolubility along withRatio is a parabolical change, and when PTX addition is less, its dissolubility is also the most relatively
Low, along with the increase of ratio, the dissolubility of PTX also increases sharply, whenDuring left and right, dissolubility reaches maximum
Value 3.6mg/ml.Now continue increase PTX amount, its dissolubility is declined slightly on the contrary, illustrate PTX andBetween effect deposit
In optimum molar ratio, below or above this ratio, the dissolubility of PTX all can reduce.Therefore, select
Claims (2)
1. a paclitaxel complex, it is characterised in that it is acrylated cyclodextrin modified acrylic acid polymer and paclitaxel
Complex；
Described complex cyclodextrin is one or more in alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin；Paclitaxel with
Acrylated cyclodextrin modified polyacrylic mass ratio is 2:1-5；
The molecular weight of described acrylated cyclodextrin modified acrylic acid polymer is 5000 ~ 50000, wherein cyclodextrin units
With the molar ratio of acrylic acid units is between 1:4 to 1:10；The dissolubility of paclitaxel brings up to 3.6 mg/ from 0.25 μ g/ml
Ml, solubilising 14400 times；
Prepare with the following step:
1) acrylated cyclodextrin: weigh cyclodextrin that recrystallization crosses in DMF, add triethylamine and urge as positive reaction
Agent；In ice-water bath, under stirring, drip acryloyl chloride, to having reacted；After reaction being completed, mixture filters, molten with mixing
Agent method purifies product propylene acylated cyclodextrin PACD, the solid acrylated cyclodextrin PACD of collection in filtrate and is placed in vacuum tank
It is dried；
2) acrylated cyclodextrin modified polyacrylic synthesis, weighs acrylated cyclodextrin PACD and is dissolved in water, respectively
Drip different amounts of acrylic acid, under 70 DEG C of nitrogen protective conditions, cause polymerization, react and complete for 1-2 hour；Solution is through dialysing, freezing
Dry it is dried to obtain acrylated cyclodextrin modified polyacrylic acid CDPAA；
3) paclitaxel is dissolved in a small amount of ethanol, paclitaxel ethanol solution is added acrylated cyclodextrin modified polypropylene
In aqueous acid, mixed solution is sealed and is stirred at room temperature；
4) evaporating ethanol solvent, sucking filtration removes the paclitaxel having neither part nor lot in inclusion, gained filtrate is spin-dried for, vacuum drying, i.e.
Prepare the complex of acrylated cyclodextrin modified acrylic acid polymer and paclitaxel.
2. by the paclitaxel complex described in claim 1 preparation tumor in application.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1123030A (en) * | 1993-05-12 | 1996-05-22 | 奇诺英有限公司 | Inclusion complexes of taxol or taxotere or taxus extract formed with cyclodextrins, its preparation and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1123030A (en) * | 1993-05-12 | 1996-05-22 | 奇诺英有限公司 | Inclusion complexes of taxol or taxotere or taxus extract formed with cyclodextrins, its preparation and use |
Non-Patent Citations (1)
| Title |
|---|
| "β-环糊精-聚丙烯酸的合成及对β-环糊精的包结与增溶性";韩晓鹃等;《高分子材料科学与工程》;20120930;第28卷(第9期);第13-16页 * |
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