CN103920163A - Paclitaxel compound, and preparation method and application thereof - Google Patents
Paclitaxel compound, and preparation method and application thereof Download PDFInfo
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- CN103920163A CN103920163A CN201410095972.3A CN201410095972A CN103920163A CN 103920163 A CN103920163 A CN 103920163A CN 201410095972 A CN201410095972 A CN 201410095972A CN 103920163 A CN103920163 A CN 103920163A
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- paclitaxel
- cyclodextrin
- complex
- propylene
- pacd
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- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 59
- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 58
- -1 Paclitaxel compound Chemical class 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 8
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims abstract description 56
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 35
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 30
- 239000004584 polyacrylic acid Substances 0.000 claims abstract description 28
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 26
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 8
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 201000004216 Posterior amorphous corneal dystrophy Diseases 0.000 claims abstract 4
- 108700027610 cytoplasmic protein A Proteins 0.000 claims abstract 4
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000007809 chemical reaction catalyst Substances 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000006116 polymerization reaction Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000000502 dialysis Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 abstract description 7
- 229920000642 polymer Polymers 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 230000010933 acylation Effects 0.000 abstract description 3
- 238000005917 acylation reaction Methods 0.000 abstract description 3
- 238000007334 copolymerization reaction Methods 0.000 abstract description 3
- 238000013459 approach Methods 0.000 abstract description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 abstract 4
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 abstract 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 abstract 1
- 230000003381 solubilizing effect Effects 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000002708 enhancing effect Effects 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000693 micelle Substances 0.000 description 3
- 238000010526 radical polymerization reaction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 2
- 235000019394 potassium persulphate Nutrition 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 235000005135 Micromeria juliana Nutrition 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000246354 Satureja Species 0.000 description 1
- 235000007315 Satureja hortensis Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002657 fibrous material Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- SWINCIBSAYTBMF-UHFFFAOYSA-N n-(pyridin-2-ylmethyl)pyridine-3-carboxamide Chemical compound C=1C=CN=CC=1C(=O)NCC1=CC=CC=N1 SWINCIBSAYTBMF-UHFFFAOYSA-N 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
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- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a paclitaxel compound which is a compound of acryloylated cyclodextrin modified polyacrylic polymer and paclitaxel. Cyclodextrin (CD) in the compound is one or more selected from the group consisting alpha-CD, beta-CD and gamma-CD. The mass ratio of paclitaxel to acryloylated CD modified polyacrylic acid is 2: 1-5. The molecular weight of the acryloylated cyclodextrin modified polyacrylic polymer is 5000 to 50000, wherein a molar ratio of a CD unit to an acrylic acid unit is in a range of 1: 4 to 1: 10. Acryloylated beta-CD (PACD) is synthesized at first by using acylation between beta-CD and acryloyl chloride; and then beta-CD modified polyacrylic acid (CDPAA) is directly prepared in an aqueous solution through radical copolymerization. The compound formed by CDPAA and paclitaxel can exert a solubilizing effect on paclitaxel and enables solubility of paclitaxel to be increased from 0.25 mu g/ml to 3.6 mg/ml, so a novel feasible approach is provided for clinical application of the anti-cancer drug--paclitaxel.
Description
Technical field:
The present invention relates to the water miscible complex of a kind of enhancing anti-cancer medicine paclitaxel, preparation and application.
Background technology:
Paclitaxel (Paclitaxel, PTX) is a kind of very effective antitumor drug, is mainly used in treating ovarian cancer and breast carcinoma.But its clinical value can not get a desired effect, be mainly because the non-constant of its dissolubility in water.Simultaneously, in PTX, lacking can Ionized functional group, and solution ion strength or pH value are little on its dissolubility impact, therefore guarantee do not losing under the condition of its property of medicine, by functional group, be converted and increase its dissolubility, for the clinical practice of paclitaxel, have very large meaning.Therefore, the lyotropy of PTX becomes a very important problem.
Existing studies show that: PTX is loaded in the polymer micelle of some inner hydrophobic, these micelle outsides are hydrophilic, so just can stable existence in aqueous solution, be so just equivalent to increase the water solublity of PTX.Some have the auxiliary agent of remarkable result as N-picolylnicotinamide(PNA to the solubilising of PTX) etc. be also introduced in block macromolecular micelle, for strengthening PTX at the dissolubility of water.
Cyclodextrin (Cyclodextrin is called for short CD) is to be passed through by some glucose units
glycosidic bond in conjunction with and the chiral ring oligosaccharide compound that forms.According to construction unit number, cyclodextrin can be divided into respectively by 6,7,8 glucose units form
(Fig. 5), it is round table-like that their structure is all, and inside is a hydrophobic cavity with certain size, can enclose hydrophobic guest molecules.Cyclodextrin and micromolecule derivant thereof are the newtype drug enclose materials receiving much concern in recent years, they can improve some character of medicine, make it be easy to allotment and take, and strengthen the stability of medicine, reduce the toxic and side effects of medicine, strengthen the bioavailability of medicine.
Cyclodextrin is introduced to some polymeric system and can retain its cavity and more hydroxyl, just for the guest molecules such as cyclodextrin and Organic substance, inorganic matter are combined, provide may for this.So just be equivalent to combine the dual-use function of polymeric material and cyclodextrin, even can produce some new performances, can prepare as required functional material.For example cyclodextrin is fixed to cellulose surface, is processing accordingly, just can prepare the fibrous material of savory, drug effect, moisturizing, the various performances such as anticorrosion.Can be for gene and drug conveying to the macromole of preparing on cyclodextrin by poly-sub-ethamine-polyvinyl alcohol graft copolymerized.
Polyacrylic acid (polyacrylic acid, PAA) aqueous stability is fabulous, is difficult for corruption, has good biocompatibility, has a wide range of applications, as can be used as gastric mucosa protectant etc. at food, field of medicaments.The invention provides and adopt the polyacrylic acid composite of cyclo-dextrin-modified to strengthen the deliquescent method of paclitaxel.
Summary of the invention:
The object of the present invention is to provide the water miscible complex of a kind of enhancing anti-cancer medicine paclitaxel, preparation method and application.Utilize the acylation between cyclodextrin and acryloyl chloride, first synthesized propylene acylated cyclodextrin.Then directly in aqueous solution, pass through radical copolymerization legal system for cyclodextrin modified polyacrylic acid.
polyacrylic acid and the paclitaxel modified are compound, can make paclitaxel water-soluble rapidly, and the dissolubility of paclitaxel is brought up to 3.6mg/ml from 0.25 ì g/ml, 14400 times of solubilisings.
Paclitaxel complex, the complex of the cyclodextrin modified acrylic acid polymer of propylene acidylate and paclitaxel.
In described complex, cyclodextrin is
in one or more.
The molecular weight of polymer is 5000~50000, wherein the molar ratio of cyclodextrin unit and acrylic acid units at 1:4 between 1:10.
The water miscible complex of enhancing anti-cancer medicine paclitaxel of the present invention, can bring up to 3.6mg/ml from 0.25 ì g/ml by the dissolubility of paclitaxel, 14400 times of solubilisings.
The preparation method of described paclitaxel complex, comprises the following steps:
1) propylene acidylate
(PACD) synthetic, takes that recrystallization crosses
be dissolved in DMF, add triethylamine as positive reaction catalyst.In ice-water bath, stir the lower acryloyl chloride that drips, to reacting, substantially complete.Mixture is filtered, and with product P ACD in mixed solvent method purification filtrate, it is dry that the solid PACD of collection is placed in vacuum tank.
2)
modify the synthetic of polyacrylic acid (chain) CDPAA, take PACD and be dissolved in water, drip respectively not commensurability acrylic acid, initiated polymerization under 70 ℃ of nitrogen protection conditions, reacts about 1-2 hour and completes.Solution obtains through dialysis, lyophilization
the polyacrylic acid (CDPAA) of modifying.
3) paclitaxel is dissolved in a small amount of ethanol, paclitaxel alcoholic solution is added
in polyacrylic acid (CDPAA) aqueous solution of modifying, by mixed solution sealing at room temperature stirring.
4) alcohol solvent is removed in evaporation, and sucking filtration is removed the paclitaxel that has neither part nor lot in inclusion, and gained filtrate is spin-dried for, and vacuum drying, prepares
polyacrylic acid CDPAA and the paclitaxel complex modified.
The application of the paclitaxel complex that above-mentioned preparation method obtains in medicine for treating tumor thing.
Beneficial effect of the present invention: by directly standby by radical copolymerization legal system in aqueous solution
the polyacrylic acid (CDPAA) of modifying.Gained paclitaxel complex solid product is through proofs such as infrared spectrum, NMR (Nuclear Magnetic Resonance) spectrum.The cyclodextrin modified acrylic acid polymer of the present invention is as a kind of low toxicity and pharmaceutical carrier soluble in water, anti-cancer medicine paclitaxel is being carried out after inclusion, the dissolubility of this medicine in water improves greatly, can be by the dissolubility of paclitaxel from bringing up to 3.6mg/ml from 0.25 ì g/ml.Thereby solve the key issue of anti-cancer medicine paclitaxel in application.The formed complex of CDPAA paclitaxel that the present invention is prepared, thus to the clinical practice of anti-cancer medicine paclitaxel, provide a kind of new feasible approach.
Accompanying drawing explanation:
Fig. 1
the infrared spectrogram of PACD, CDPAA, PAA.
Fig. 2
the nuclear magnetic spectrogram of PACD and CDPAA.
Fig. 3
modify the dissolubility picture of polyacrylic acid and paclitaxel complex.
Fig. 4
modify polyacrylic synthetic route chart.
Fig. 5
structural representation.
The specific embodiment:
Embodiment, the method that the present invention prepares cyclodextrin modified polyacrylic acid and paclitaxel complex is as follows:
1) propylene acidylate
-cyclodextrin propylene acidylate CD's is synthetic
Take the CD that recrystallization crosses and be dissolved in the DMF of excessive (more than five times of CD quality), transfer in three-necked bottle, add triethylamine (as 0.5-2 times of CD quality) as positive reaction catalyst.Three-necked bottle is placed in ice-water bath, under magnetic agitation condition, with Dropping funnel, drips acryloyl chloride, continues stir about half an hour under room temperature, and reaction completes substantially.Mixture is filtered, discard filtering residue, filtrate is transferred in conical flask.With mixed solvent method (acetone methanol) purified product (acetone is both poor solvents, and methanol is two solvents of product, the poor solvent of raw material), add acetone precipitation to go out product cyclo-dextrin-modified acrylate monomer (PACD) and unreacted complete
filter, discard mother solution.Solid is partly dissolved with methanol, filters, and discards filtering residue.Filtrate continuation goes out solid with acetone precipitation, collects solid product PACD, so repeats 1~2 time, until filtrate is detected without chloride ion through silver nitrate.It is dry that the solid PACD collecting is placed in vacuum tank, 30~40 ℃ of temperature.
CD is
all can.
2) propylene acidylate CD modifies the synthetic of polyacrylic acid chain,
Taking PACD is dissolved in water; drip 0.5-2 that a certain amount of acrylic acid (AA) AA is PACD doubly, from 10:1 to 4:1 not etc., oil bath is heated to 70 ℃ to the ratio that makes AA:CD; under nitrogen protection condition, add a certain amount of potassium peroxydisulfate initiated polymerization, react after approximately 1.5 hours and stop.Solution is transferred in bag filter and is dialysed, and lyophilizing after solution cooled with liquid nitrogen is collected, to be analyzed.Prepare the polyacrylic acid that CD modifies.
3) paclitaxel is dissolved in a small amount of ethanol, then joins in the polyacrylic acid aqueous solution of propylene acidylate CD modification, stir, mixed solution is at room temperature stirred 12 hours.The polyacrylic mass ratio that paclitaxel and propylene acidylate CD modify is 2:1-5.
4) reduction vaporization is removed alcohol solvent, and sucking filtration is removed the paclitaxel that has neither part nor lot in inclusion, and gained filtrate is spin-dried for, and vacuum drying, prepares polyacrylic acid and paclitaxel complex that CD modifies.
Cyclodextrin modified acrylic acid polymer involved in the present invention and paclitaxel complex are synthetic as follows, and we choose
for representative cyclodextrin is illustrated:
1)
modify polyacrylic synthetic
Take that recrystallization crosses
8.0g is dissolved in 20ml DMF, transfers in 100ml three-necked bottle, adds 3ml triethylamine as positive reaction catalyst.Three-necked bottle is placed in ice-water bath, under magnetic agitation condition, with Dropping funnel, drips 3ml acryloyl chloride, controls rate of addition at 1d/s~2d/3s.Drip to finish, room temperature (25~30 ℃) is lower continues stir about half an hour, and reaction completes substantially.Mixture is filtered, discard filtering residue, filtrate is transferred in 150ml conical flask.With mixed solvent method purified product (acetone is both poor solvents, and methanol is two solvents of product, the poor solvent of raw material), add 100ml acetone precipitation to go out product PACD and unreacted complete
filter, discard mother solution.Solid is partly dissolved with 20ml methanol, filters, and discards filtering residue.Filtrate continuation goes out solid with 100ml acetone precipitation, collects solid product PACD, so repeats 1~2 time, until filtrate is detected without chloride ion through silver nitrate.It is dry that the solid PACD collecting is placed in vacuum tank, 30~40 ℃ of temperature.
Take 0.2g PACD and be dissolved in 20ml water, drip a certain amount of acrylic acid, make AA:
ratio from 10:1 to 4:1 not etc., oil bath is heated to 70 ℃, adds a certain amount of potassium peroxydisulfate initiated polymerization under nitrogen protection condition, reacts after approximately 1.5 hours and stops.Solution is transferred to dialysis 48h in bag filter (molecular weight is removed below 3500), changes water 3~4 times, and lyophilizing after solution cooled with liquid nitrogen, collects, to be analyzed.Prepare
the polyacrylic acid of modifying.
2)
synthesizing of the polyacrylic acid of modifying and paclitaxel complex
Paclitaxel is dissolved in a small amount of ethanol, joins
in the polyacrylic acid aqueous solution of modifying, stir, by mixed solution sealing at room temperature stirring.Alcohol solvent is removed in evaporation, and sucking filtration is removed the paclitaxel that has neither part nor lot in inclusion, and gained filtrate is spin-dried for, and vacuum drying, prepares
polyacrylic acid and the paclitaxel complex modified.
3)
the polyacrylic acid of modifying and the sign of paclitaxel complex
the polyacrylic acid of modifying characterizes by the following method:
Infrared spectrum (Bruker Vector22 infrared spectrometer)
PACD, CDPAA, polyacrylic acid (PAA) and raw material
infrared spectrogram relatively see Fig. 1,
at 1500cm
-1-2000cm
-1the obvious absworption peak of nothing in scope, and PACD is at 1727cm
-1and 1663cm
-1there are two strong absworption peaks at place, belongs to respectively the stretching vibration of C=O and C=C, illustrates that acryloyl group (CH2=CH-C (=O)-) successfully received by acylation
on.
characteristic absorption peak mainly concentrate on finger print region (pyranoid ring C-O stretching vibration 1035cm
-1) in, these characteristic peaks can observe in PACD spectrogram, explanation
successfully be linked into PACD upper, prepared
the acrylate monomer of modification.And in CDPAA spectrogram, 1663cm
-1place belongs to the characteristic peak of the two keys of C=C, becomes very weak in CDPAA spectrogram, substantially can ignore.This is because the two keys of C=C have participated in radical polymerization, become singly-bound, so characteristic peak has not herein existed.1418cm
-1double key carbon hydrogen bonds peak, place also disappears substantially, and both have confirmed that two keys are to the transformation of singly-bound simultaneously.This explanation PACD has participated in radical polymerization well, has confirmed the successfully preparation of acrylate polymer of cyclo-dextrin-modified.
NMR (Nuclear Magnetic Resonance) spectrum (Bruker DRX500 nuclear magnetic resonance chemical analyser)
In order further to confirm
the polyacrylic structure of modifying, carries out HNMR analysis by product, the results are shown in Figure 2.
in construction unit, the chemical shift of hydrogen atom ownership is respectively:
these proton peak can be observed in the spectrogram of PACD and CDPAA.Relatively PACD with
spectrogram, one significantly changes is that the former is many
the proton peak at place, this is two key proton peak, i.e. proton peak in acryloyl group.The existence at this peak, explanation
really propylene acidylate.But this peak has but disappeared in CDPAA, two key generation radical polymerization is described, become singly-bound, the substitute is
near and the alkyl proton peak 2.1.
Dissolubility
thering is considerable influence aspect enhancing PTX dissolubility, therefore studied in main polymer chain the impact of different PTX content on PTX dissolubility.Fig. 3 is different
pTX dissolubility picture under ratio.As we can see from the figure, the dissolubility of PTX along with
ratio is a parabolical variation, and when PTX addition is less, its dissolubility is also corresponding lower, and along with the increase of ratio, the dissolubility of PTX also increases sharply, when
during left and right, dissolubility reaches maximum 3.6mg/ml.Now continue to increase the amount of PTX, its dissolubility slightly declines on the contrary, illustrate PTX and
between effect there is optimum molar ratio, below or above this ratio, the dissolubility of PTX all can reduce.Therefore, select
Claims (6)
1. a paclitaxel complex, is characterized in that it is the complex of the cyclodextrin modified acrylic acid polymer of propylene acidylate and paclitaxel.
2. by paclitaxel complex claimed in claim 1, it is characterized in that in described complex, cyclodextrin is
in one or more; The polyacrylic mass ratio that paclitaxel and propylene acidylate CD modify is 2:1-5.
3. by paclitaxel complex claimed in claim 1, it is characterized in that the molecular weight of the described cyclodextrin modified acrylic acid polymer of propylene acidylate is 5000~50000, wherein the molar ratio of cyclodextrin unit and acrylic acid units at 1:4 between 1:10.
4. by paclitaxel complex claimed in claim 1, it is characterized in that the dissolubility of paclitaxel to bring up to 3.6mg/ml from 0.25 ì g/ml 14400 times of solubilisings.
5. by the preparation method of paclitaxel complex claimed in claim 1, it is characterized in that comprising the following steps:
1) propylene acylated cyclodextrin: take the cyclodextrin CD that recrystallization crosses and be dissolved in DMF, add triethylamine as positive reaction catalyst; In ice-water bath, stir the lower acryloyl chloride that drips, to having reacted; After reaction is completed, mixture filters, and with product propylene acylated cyclodextrin PACD in mixed solvent method purification filtrate, it is dry that the solid propylene acylated cyclodextrin PACD of collection is placed in vacuum tank.
2) propylene acidylate is cyclodextrin modified polyacrylic synthetic, takes propylene acylated cyclodextrin PACD and is dissolved in water, drips respectively not commensurability acrylic acid, and initiated polymerization under 70 ℃ of nitrogen protection conditions, reacts about 1-2 hour and complete; Solution obtains through dialysis, lyophilization
the polyacrylic acid (CDPAA) of modifying.
3) paclitaxel is dissolved in a small amount of ethanol, paclitaxel alcoholic solution is added in the cyclodextrin modified polyacrylic acid aqueous solution of propylene acidylate, by mixed solution sealing at room temperature stirring;
4) alcohol solvent is removed in evaporation, and sucking filtration is removed the paclitaxel that has neither part nor lot in inclusion, and gained filtrate is spin-dried for, and vacuum drying, prepares the complex of the cyclodextrin modified acrylic acid polymer of propylene acidylate and paclitaxel.
6. the application in medicine for treating tumor thing by the paclitaxel complex obtaining one of claim 1-5 Suo Shu.
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CN112107731A (en) * | 2020-09-24 | 2020-12-22 | 武汉理工大学 | Injectable double-layer drug-loaded osteochondral repair hydrogel scaffold and preparation method thereof |
Citations (1)
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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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 (2)
Title |
---|
HAILAN KE ET AL.: ""ALPHA-CYCLODEXTRIN MODIFIED POLY(ACRYLIC ACID) AND TUNABLE NETWORKS BASED ON ITS HOST-GUEST COMPLEXATION"", 《POLYMER PREPRINTS》 * |
韩晓鹃等: ""β-环糊精-聚丙烯酸的合成及对β-环糊精的包结与增溶性"", 《高分子材料科学与工程》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112107731A (en) * | 2020-09-24 | 2020-12-22 | 武汉理工大学 | Injectable double-layer drug-loaded osteochondral repair hydrogel scaffold and preparation method thereof |
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