CN102266568A - Preparation method for hydroxypropyl cyclodextrin inclusion of taxol - Google Patents
Preparation method for hydroxypropyl cyclodextrin inclusion of taxol Download PDFInfo
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- CN102266568A CN102266568A CN 201110217848 CN201110217848A CN102266568A CN 102266568 A CN102266568 A CN 102266568A CN 201110217848 CN201110217848 CN 201110217848 CN 201110217848 A CN201110217848 A CN 201110217848A CN 102266568 A CN102266568 A CN 102266568A
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- cyclodextrin
- taxol
- paclitaxel
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Abstract
The invention discloses a preparation method for a hydroxypropyl cyclodextrin inclusion of taxol, and belongs to the technical field of preparation of water-soluble medicaments in the technical field of super-molecular inclusion. Hydroxypropyl-cyclodextrin serving as host molecules, taxol serving as guest molecules and N,N-dimethyl formamide serving as a reaction solvent are subjected to homogeneous super-molecular reaction to generate the water-soluble taxol super-molecular inclusion. The purity of the inclusion product prepared by the method is high; and the method is simple and convenient in operation, controllable in conditions and easy for industrialized production. The prepared taxol-cyclodextrin super-molecular inclusion has good water solubility, the solubility of the inclusion in the water of 25 DEG C is 0.26mg/ml, the structure of the inclusion is stable, and the structure and the medicinal performance of the taxol are not destroyed. Due to excellent water solubility of the taxol-hydroxypropyl cyclodextrin inclusion, the taxol which is a natural anti-cancer medicament with poor water solubility is expected to become an oral medicament or intravenous injection.
Description
Technical field
The invention belongs to the preparing technical field of supermolecule inclusion technique field water soluble drug.
Background technology
Paclitaxel (Paclitaxel) is the diterpene-kind compound of a complexity, molecular formula: C
47H
51NO
14, molecular weight: 853.918, white crystal.Paclitaxel is more stable in pH4～8 scopes, and very fast decomposition is more stable under the acid condition under the alkali condition.Paclitaxel from the Ramulus et folium taxi cuspidatae bark separation and Extraction to a kind of natural antitumor material.The active anticancer mechanism of paclitaxel uniqueness is that it belongs to mitotic inhibitor or spindle poison, not only can suppress the formation of mitosis, spindle and the spindle fiber of cell, thereby stop the breeding of cancerous cell, and can be by inducing and promote the polymerization and the assembling of tubulin, stop microtubule generation depolymerization, make microtubule stable, thereby for the tumor of many medicines of anti-the conventional chemotherapy activity is arranged, application prospect is very wide.But paclitaxel at room temperature is difficult to water-soluble and many medicinal solvents, and dissolubility only is 0.006 mgmL in water
-1, oral being difficult to absorbs, and uses intravenous administration usually.The formulation for paclitaxel that uses clinically mainly is that (50:50 V/V) mixes as solvent, makes injection with dehydrated alcohol with polyoxyethylene castor oil (CrEL) at present.Because the large usage quantity of CrEL severe anaphylactic reaction can occur after the intravenous drip in the said preparation, therefore before administration, patient needs in advance with corticoid and antihistaminic to alleviate anaphylaxis.Must be diluted to 0.3-1.2mg/ml with the CrEL-dehydrated alcohol in use as the formulation for paclitaxel of solvent and instil, but this diluent can only keep stablizing in 12-24h.
As second filial generation supermolecule main block chemical compound---cyclodextrin (Cyclodextrins, letter is CDs), be with а-1 by 6 above D-glucopyranose units, one class cyclic oligosaccharide of 4 bondings according to the difference of its contained glucose unit number, can be divided into а-CD, β-CD and γ-CD etc., wherein (β-CD) output is the highest, and price is the most cheap, and is most widely used general with beta-schardinger dextrin-again.Therefore the characteristics of cyclodextrin compounds are the hydrophobicity cavitys that all has certain size, enclose multiclass guest molecule and form super molecular compound selectively.Because its unique texture makes the theoretical research of cyclodextrin and practical application all obtain to develop rapidly.At aspects such as industry, agricultural, food, medicine, isolation technics and environmental conservation important use is arranged all.
The cage structure of beta-schardinger dextrin-uniqueness can form clathrate by the enclose drug molecule, this moment, drug molecule was contained in β-CD molecule cavity, has very high dispersion, simultaneously because the outside polyhydric hydrophilic of β-CD, make clathrate have good wettability, thereby reach solubilizing effect insoluble drug.Because β-CD autolysis degree is lower, usually introduces modification group and improve its dissolubility, to enlarge its range of application at its edge.Hydroxypropyl in numerous cyclodextrin derivative-
-cyclodextrin (HP-
-CD) be considered to one of the most useful cyclodextrin derivative, be food and drug administration (Food and Drug А dministration, FD А) but first injection for intravenous of approval
-CD derivant has that toxicity is low, hemolytic is low and the characteristics of good water solubility.HP-
-CD is
The hydrophilic derivatives that-CD and 1,2 epoxy prapane condensation form.By right
The hydroxypropylation of-CD destroys its intramolecular hydrogen bond, and its water solublity is significantly improved.
The water solublity of-CD at room temperature be about 1.85% (
W/v), and HP-
-CD is then soluble in water, dissolubility under the room temperature〉50% (
W/v), even can be up to 75% (
W/v) more than, when its concentration＜40% (
W/v), good fluidity, not thickness.High water solublity and molecular flexibility make HP-
-CD can form non-covalent complex with the drug molecule enclose well, therefore can improve stability of drug, water solublity, reduces the volatility of medicine, and control drug release speed is covered bad smell etc.This in addition enclose material has characteristics such as nephrotoxicity is low, haemolysis is little, local irritation is slight, and this makes insoluble drug make injection becomes possibility.
At present, paclitaxel-hydroxypropyl-
The existing report of-Preparation methods of cyclodextrin inclusion complexes mainly is to adopt mixed solvent method to carry out inclusion reaction.Its preparation method: the mass ratio of paclitaxel and cyclodextrin is 1:10 ~ 150, in cyclodextrin aqueous solution, drip the alcoholic solution of paclitaxel, system dissolving back is with 0.2～0.4 μ m filtering with microporous membrane, filtrate decompression is removed ethanol, decompression dewaters, and lyophilization obtains solid clathrates, or decompression obtains liquid clathrate after removing ethanol, and wherein ethanol content is less than 2%.
The defective of prior art is:
1, in the preparation process, for medicine is wrapped in the cavity of cyclodextrin as much as possible, the consumption of host compound is often much larger than amount of drug (mass ratio 10 ~ 150:1), cause containing in the final products a large amount of host compounds, can't guarantee the purity of clathrate, for next step drug level determine impact, simultaneously also be waste to raw material.
2, adopt mixed solvent method to prepare super molecule inclusion compound, because paclitaxel dissolubility in water is minimum, in mixed solvent, having the part paclitaxel can not dissolve, and inclusion reaction is not to carry out in homogeneous system, on the one hand, inclusion reaction can not fully carry out, and productive rate is lower; On the other hand, inclusion reaction needs with microporous filter membrane reaction system to be filtered after finishing, and has removed Yet-have unreacted or dissolved paclitaxel, has improved the clathrate preparation cost virtually.
3, adopt mixed solvent method, operation is comparatively complicated, and subsequent treatment is comparatively loaded down with trivial details, and the energy consumption height needs distilling under reduced pressure to remove second alcohol and water etc.
Summary of the invention
The objective of the invention is to propose the preparation method of a kind of new type water-solubility paclitaxel-cyclodextrin super molecule inclusion compound, be intended to overcome above-mentioned defective, adopt more easy method to prepare highly purified clathrate.
Technical solution of the present invention is: with hydroxypropyl-
-cyclodextrin and paclitaxel are dissolved in N, in the dinethylformamide, are under 15～35 ℃ the condition in temperature, stirring reaction; Question response adds methanol after finishing again, separates out white solid; With the white solid sucking filtration, filter cake is placed on 30～50 ℃ of vacuum dryings through absolute ethanol washing, obtain water-soluble paclitaxel-hydroxypropyl-
-cyclodextrin clathrate.
The present invention with hydroxypropyl-
-cyclodextrin is that host molecule, paclitaxel are guest molecule, N, and dinethylformamide is a reaction dissolvent, the reaction of homogeneous phase supermolecule takes place generate the water-soluble paclitaxel super molecule inclusion compound.DMF can dissolve simultaneously hydroxypropyl-
-cyclodextrin and paclitaxel make inclusion reaction carry out in homogeneous phase solution, improve the efficient of reaction.This method prepares clathrate product purity height, and easy and simple to handle, condition is easily controlled, and is easy to suitability for industrialized production.The use hydroxypropyl-
-cyclodextrin and paclitaxel common broad dose makes inclusion reaction in homogeneous phase solution.Utilizing clathrate dissolubility in methanol relatively poor, is precipitant with methanol, makes clathrate precipitation, pass through sucking filtration, washing, drying again after, can obtain paclitaxel-hydroxypropyl cyclodextrin clathrate.Paclitaxel-cyclodextrin super molecule inclusion compound the good water solubility of preparation, the dissolubility in 25 ℃ of water is 0.26 mg/ml, Stability Analysis of Structures is not destroyed the structure and the pharmaceutical characteristic of paclitaxel self.Paclitaxel-good the water solublity of hydroxypropyl cyclodextrin clathrate makes to be expected to make oral drugs or intravenous injection injection by the relatively poor natural anti-cancer drugs of this water solublity of paclitaxel.
In order to improve the purity of clathrate, described hydroxypropyl-
The molar ratio of-cyclodextrin and paclitaxel is 1 ︰ 5～10.
Description of drawings
Fig. 1 isThe hydroxypropyl cyclodextrin clathrate of the water-soluble paclitaxel that employing the inventive method is made and the infrared spectrogram of host and guest compound.
The specific embodiment
In order to make purpose of the present invention, technical scheme and advantage clearer, the present invention is described in detail below in conjunction with embodiment.
1, in 250 mL conical flasks, add 0.1 mol hydroxypropyl-
-cyclodextrin and 0.5～1 mol paclitaxel, Subjective and Objective molecule mol ratio is 1 ︰ 5～10, is dissolved in 100 ml N, dinethylformamide (DMF).15～35 ℃ of reaction temperatures, magnetic agitation or mechanical agitation 24 h.
2, after question response finishes, add precipitation agent methanol 20～50 ml in conical flask, the adularescent solid is separated out in the reaction system.Sucking filtration solid, filtrate keep also and are transferred in the round-bottomed flask, and a small amount of absolute ethanol washing of filter cake then places 30～50 ℃ of vacuum drying 24 h with solid, obtains white solid, be water-soluble paclitaxel-hydroxypropyl-
-cyclodextrin clathrate.
3, will more than be transferred to filtrate in the round-bottomed flask, carry out distilling under reduced pressure earlier, remove methanol in the filtrate (methanol that distills out also can recycling), contain in the residual filtrate a large amount of not by the guest molecule paclitaxel of enclose, can continue to add hydroxypropyl-
-cyclodextrin carries out inclusion reaction, repeats aforesaid operations, need not to change solvent.The amount of substance concentration that should keep guest molecule is more than 2 times of host molecule amount of substance concentration.Whole process does not almost have solvent loss.
4, product adopts infrared spectrum to identify.Infrared spectrum is recorded by Bruker-Tensor 27 infrared spectrometers.Shown in Figure 1, (a) is the infrared spectrogram of paclitaxel among the figure, and the carbonyl of paclitaxel-C=O vibration and two key-C=C vibration absorption peak are all respectively at 1731 cm
-1With 1648 cm
-1(b) be the infrared spectrogram of hydroxypropyl cyclodextrin.(c) be paclitaxel-hydroxypropyl cyclodextrin clathrate infrared spectrogram, (c) in identical wave number place the two key chattering absworption peaks of carbonyl and C=C have appearred, show thus paclitaxel entered into hydroxypropyl-
In the cavity of-cyclodextrin, formed super molecule inclusion compound.
Claims (2)
1. the preparation method of the hydroxypropyl cyclodextrin clathrate of a paclitaxel is characterized in that: with hydroxypropyl-
-cyclodextrin and paclitaxel are dissolved in N, in the dinethylformamide, are under 15～35 ℃ the condition in temperature, stirring reaction; Question response adds methanol after finishing again, separates out white solid; With the white solid sucking filtration, filter cake is placed on 30～50 ℃ of vacuum dryings through absolute ethanol washing, obtain water-soluble paclitaxel-hydroxypropyl-
-cyclodextrin clathrate.
2. according to the preparation method of the hydroxypropyl cyclodextrin clathrate of the described paclitaxel of claim 1, it is characterized in that: described hydroxypropyl-
The molar ratio of-cyclodextrin and paclitaxel is 1 ︰ 5～10.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641925A (en) * | 2012-11-27 | 2014-03-19 | 王晖 | Covalent polycompound of water-soluble polysaccharide and taxane compound, and preparation method and medical application of covalent polycompound |
| CN106309411A (en) * | 2016-09-23 | 2017-01-11 | 潍坊医学院 | Quercetin and paclitaxel co-transportation pulmonary inhaled nanometer targeted porous polymer particle and preparation method thereof |
| CN110292643A (en) * | 2019-07-22 | 2019-10-01 | 中国药科大学 | A kind of preparation method of lycopene/cyclodextrin inclusion compound |
| CN114085298A (en) * | 2021-11-30 | 2022-02-25 | 扬州大学 | Water-soluble supramolecular inclusion compound DPG and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1379047A (en) * | 2002-05-10 | 2002-11-13 | 刘云清 | Match of organic medicine and beta-cyclodextrin derivative and its preparing process |
| CN1424112A (en) * | 2002-12-17 | 2003-06-18 | 上海医药工业研究院 | Water soluble dressing for insoluble medicines and preparation thereof |
| CN1589157A (en) * | 2001-11-19 | 2005-03-02 | 维亚尼克斯公司 | Inclusion complex of taxol with 2-hydroxypropyl-beta-cyclodextrin |
-
2011
- 2011-08-01 CN CN 201110217848 patent/CN102266568A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1589157A (en) * | 2001-11-19 | 2005-03-02 | 维亚尼克斯公司 | Inclusion complex of taxol with 2-hydroxypropyl-beta-cyclodextrin |
| CN1379047A (en) * | 2002-05-10 | 2002-11-13 | 刘云清 | Match of organic medicine and beta-cyclodextrin derivative and its preparing process |
| CN100467494C (en) * | 2002-05-10 | 2009-03-11 | 刘云清 | Organic medicine and betacyclodextrin derivative and preparation process thereof |
| CN1424112A (en) * | 2002-12-17 | 2003-06-18 | 上海医药工业研究院 | Water soluble dressing for insoluble medicines and preparation thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641925A (en) * | 2012-11-27 | 2014-03-19 | 王晖 | Covalent polycompound of water-soluble polysaccharide and taxane compound, and preparation method and medical application of covalent polycompound |
| CN103641925B (en) * | 2012-11-27 | 2016-08-17 | 王晖 | Water solublity polysaccharide and the covalency polyacetylene compound of bearing taxanes, its preparation method and medical usage |
| CN106309411A (en) * | 2016-09-23 | 2017-01-11 | 潍坊医学院 | Quercetin and paclitaxel co-transportation pulmonary inhaled nanometer targeted porous polymer particle and preparation method thereof |
| CN106309411B (en) * | 2016-09-23 | 2019-05-03 | 潍坊医学院 | A kind of Quercetin and taxol convey lung sucking nano target porous polymeric particle and preparation method thereof altogether |
| CN110292643A (en) * | 2019-07-22 | 2019-10-01 | 中国药科大学 | A kind of preparation method of lycopene/cyclodextrin inclusion compound |
| CN114085298A (en) * | 2021-11-30 | 2022-02-25 | 扬州大学 | Water-soluble supramolecular inclusion compound DPG and preparation method and application thereof |
| CN114085298B (en) * | 2021-11-30 | 2022-09-16 | 扬州大学 | Water-soluble supramolecular inclusion compound DPG and preparation method and application thereof |
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Application publication date: 20111207 |