CN102293736B - Preparation process of taxol-polymer medicine-carrying micelles - Google Patents

Preparation process of taxol-polymer medicine-carrying micelles Download PDF

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CN102293736B
CN102293736B CN 201110255867 CN201110255867A CN102293736B CN 102293736 B CN102293736 B CN 102293736B CN 201110255867 CN201110255867 CN 201110255867 CN 201110255867 A CN201110255867 A CN 201110255867A CN 102293736 B CN102293736 B CN 102293736B
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dspe
paclitaxel
taxol
micelle
polymer
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CN102293736A (en
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刘伟生
周熹
窦伟
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Lanzhou University
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Abstract

The invention relates to a preparation process of taxol-polymer medicine-carrying micelles and belongs to the technical field of preparation of medicines. The preparation process comprises the following steps of: 1) preparing mixed solution of taxol and a carrier material; 2) preparing a dry lipid film and removing the residual organic solvent; 3) adding a proper amount of 0.9 percent sodium chloride solution into warm water bath, placing into a constant-temperature water bath oscillator to oscillate at constant temperature for 0.5 to 5 hours, wherein the frequency is 50 to 250 times per minute; and 4) cooling material solution obtained in the step 3) and performing membrane filtration to prepare the taxol-polymer medicine-carrying micelles, wherein the carrier material is polyethylene glycol 2000-distearoyl phosphatidyl ethanolamine (PEG2000-DSPE) or a mixture of the PEG2000-DSPE and DSPE. By the process of the invention, a new hydration method is provided, so that the properties of the micelles can be improved or remain unchanged. The PEG2000-DSPE is replaced by the cheap DSPE with considerable quantity (such as 70 percent), so the measured average grain size is still far less than the minimum average grain size of the taxol PEG2000-DSPE polymer micelle particles prepared by the traditional method.

Description

Preparation process of taxol-polymer medicine-carrying micelles
Technical field
The present invention relates to a kind of preparation process of taxol-polymer medicine-carrying micelles, belong to the medicament preparing technical field.
Background technology
As a kind of important natural anti-cancer drugs, paclitaxel possesses the drug effects such as the formation of differentiation, neovascularity of inhibition tumor cell and neoplasm metastasis, kinds cancer is had fairly obvious therapeutical effect.Yet, being subjected to the impact without target function of traditional formulation for paclitaxel, patient tends to cause very strong toxic and side effects after using.For the therapeutic effect of bringing into play this medicine and reduce its toxic and side effects, developing the Novel Drug Delivery Systems with target function is a hot subject in current medicament field.Accompany with it, pharmaceutical preparation is also progressively to future development efficient, quick-acting, that long-acting, taking dose is little, toxic and side effects is little.Wherein, the development of this class Novel Drug Delivery Systems has entered the stage of nanometer system.In recent years, has the concern that amphipathic polymer micelle particularly is subject to people.Polymer micelle originates from the 90's of 20th century as the developmental research of pharmaceutical carrier, and it is by amphipathic nature polyalcohol spontaneous a kind of self-assembled structures that forms in aqueous solution.Its hydrophilic fragment (as Polyethylene Glycol) forms shell, hydrophobicity fragment (as DSPE) forms kernel, and the nucleocapsid structure of the uniqueness that consists of thus can be stated from the insoluble drug bag in kernel.That is in the developmental research of the drug-supplying system of current this medicine, the main a kind of amphiphilic block copolymers PEG that adopts 2000-DSPE, but self assembly forms the nano-micelle system of spherical nucleocapsid structure in aqueous solution, and wherein hydrophobic block formation kernel bag carries paclitaxel, greatly increases the water solublity of paclitaxel, evade simultaneously the supervision layer by layer of vivo immuning system, thereby extended the time of medicine in blood circulation.Because the polymer micelle particle diameter is generally less than 100 nm, the characteristics such as drug loading is high therefore its drug-supplying system has, the medicine carrying scope wide, good stability, the interior holdup time length of body, medicine stability and bioavailability have effectively been improved, alleviated untoward reaction, also can connect the targeted molecular with specific recognition function on the surface simultaneously, realize initiatively target administration.
At existing paclitaxel PEG 2000In the preparation process of-DSPE medicine carrying system of polymer micelle, its hydration process technique adopts mechanical agitation or vortex method to carry out, and the minimum grain size that can prepare is near 50nm, and distributed areas reach , this makes its micelle administration system possess certain targeting.We know, being grain refine by the particle diameter that reduces polymer micelle all can improve the targeting of drug-supplying system with the uniformity that improves particle size distribution (namely reduce particle size distribution interval).Therefore, at paclitaxel PEG 2000Under the enough little situation of the particle diameter of-DSPE polymer micelle, how further reducing its grain diameter is a new problem that runs in present Study on Preparation.Along with further reducing of micelle particle diameter, will promote the lifting of this class drug delivery system performance, especially aspect targeting.Secondly, due to PEG 2000Expensive this Novel Drug Delivery Systems that also restricting of-DSPE enters clinical practice.How seeking effectively, the cheap encapsulating material that substitutes replaces PEG 2000-DSPE, preparation is for the present suitable paclitaxel PEG of performance 2000-DSPE polymer micelle is also the problem that this research at present runs into.
Summary of the invention
The technical problem to be solved in the present invention is to overcome existing paclitaxel PEG 2000-DSPE polymer micelle preparation technology's cost is high, particle diameter is large, defective pockety, and a kind of new type water metallization processes is provided, and its product cut size that obtains is little, be more evenly distributed.
For this drug-supplying system, at first technique of the present invention launch the research of the further refinement of granule, after preparation technology having been proposed a kind of new aquation method and improving, confirmed prepared paclitaxel PEG 2000-DSPE polymer micelle performance obtains promote or remain unchanged, thereby has confirmed effectiveness and the reliability of this new method.At last, by cheap DSPE is substituted PEG with sizable amount 2000-DSPE(is as reaching 70%), for having prepared new paclitaxel polymer micelle administration system under new preparation process, measured mean diameter is still much smaller than not containing DSPE prepared paclitaxel PEG under traditional method 2000-DSPE polymer micelle granule minimum average particle diameters.
Particularly, the invention provides following technical scheme:
Preparation process of taxol-polymer medicine-carrying micelles comprises the steps, 1) mixed liquor of preparation paclitaxel and carrier material; 2) make dried lipid thin film and remove residual organic solvent; 3) in tepidarium, add appropriate 0.9% sodium chloride solution, constant temperature oscillation 0.5-5h, frequency is 50-250 time per minute; 4) step 3) gained feed liquid is cooling, membrane filtration namely makes paclitaxel-polymer medicament carrying micelle; Described carrier material is PEG 2000-DSPE or PEG 2000The mixture of-DSPE and DSPE.
In described step 3), constant temperature oscillation 1h, frequency is 150 times per minute.
Described PEG 2000In the mixture of-DSPE and DSPE, the mass ratio of DSPE is 10-30%.
The beneficial effect of technique of the present invention is: (1) is for paclitaxel-PEG 2000The preparation of-DSPE carrier micelle, traditional mechanical in will having preparation method stirs or the aquation method of vortex is changed into by after water bath with thermostatic control shaker enforcement constant temperature oscillation New Process for Treatment method, prepared micelle mean diameter by existing method minimum average particle diameters approximately 51nm be reduced to present mean diameter 16.1nm, thereby realized the refinement of micelle particle diameter; Meanwhile, also developed thus the new purposes (this instrument was mainly used in extracorporeal releasing experiment in the past) of water bath with thermostatic control shaker; (2) the prepared paclitaxel-PEG of new method 2000The envelop rate of-DSPE carrier micelle has improved 5% left and right, has namely surpassed 90%; Its drug loading result with traditional method is suitable, namely reaches 4.32%; (3) during the discussion that reduces costs for this medicine-carried system was studied, this technique was by partly substituting PEG with DSPE 2000Adopt the carrier micelle result that is prepared under the new technology of advising to show after-DSPE: along with the increase of replacement amount, its micelle particle diameter meansigma methods and distributed area all increase to some extent, and the stability of micelle also obviously promotes.Namely when the replacement amount reached 70%, mean diameter was 30.2nm, and this is still much smaller than the present mean diameter of the 51nm of other method; And its particle size distribution interval does not still surpass
Figure DEST_PATH_IMAGE004
, micelle stability when not containing approximately can extending in 3 days of DSPE situation and contain 70% more than 5 days.
Description of drawings
Accompanying drawing is used to provide a further understanding of the present invention, and consists of the part of description, is used for together with embodiments of the present invention explaining the present invention, is not construed as limiting the invention.In the accompanying drawings:
Fig. 1 is that the present invention adopts the paclitaxel-PEG for preparing after the constant temperature oscillation New Process for Treatment 2000The particle size distribution figure of-DSPE polymer micelle;
Fig. 2 adopts the RP-HPLC method to measure the standard curve that this inventive method prepares the content of taxol of micelle.
The specific embodiment
Below in conjunction with accompanying drawing, the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein only is used for description and interpretation the present invention, is not intended to limit the present invention.
Embodiment 1
1, paclitaxel-PEG 2000The preparation method of-DSPE carrier micelle
At room temperature precision takes a certain amount of paclitaxel (0.35mg) and carrier material PEG 2000-DSPE(10mg) after, they are placed in eggplant-shape bottle, add chloroform (1ml) and the acetonitrile (3ml) of appropriate volume, and vortex 5min, medicine and carrier material are dissolved fully and mix homogeneously.With 60r/min decompression rotary evaporation, make the dried lipid thin film at 40 ℃.After being down to room temperature, remove residual organic solvent through vacuum drying.In 37 ℃ of water-baths, add appropriate 0.9% sodium chloride solution (2ml), constant temperature oscillation is cooled to room temperature, adopts 0.22 μ m membrane filtration, thereby has prepared paclitaxel-PEG 2000-DSPE carrier micelle.
Constant temperature oscillation time and frequency are as shown in table 1.
Table 1 paclitaxel-PEG 2000Constant temperature oscillation and frequency meter in-DSPE carrier micelle grain preparation process
Duration of oscillation (h) Frequency of oscillation (beats/min)
Method 1 0.5 250
Method 2 1 150
Method 3 3 100
Method 4 5 50
2, quality determining method and the result of the product of the method 2 of table 1
), micelle is to the embedding of medicine
Recording paclitaxel by uv-spectrophotometric instrument (being the UV method) has absworption peak at 267nm and 332nm place, and after paclitaxel was aggregated the embedding of thing micelle, the absworption peak at the 332nm place weakened greatly, and this shows that paclitaxel is by the obvious embedding of micelle.
2), the particle size distribution of polymer micelle
With the above-mentioned paclitaxel-PEG that makes 2000-DSPE polymer micelle solution is put into the particle diameter pipe, adopts the particle size distribution of particle size analyzer determination micelle.Experimental result is found, the preparation-obtained paclitaxel-PEG of the present invention 2000The particle size distribution of-DSPE polymer micelle is between 12-20nm, and mean diameter is 16.1nm, as shown in Figure 1.The particle size distribution result of this result and the similar micelle of other existing method gained can find after relatively, the size of mean diameter only only have other method gained minimum average particle diameters 1/3rd, and its distributed area and the narrowest result are quite (namely
Figure 659649DEST_PATH_IMAGE002
), thereby be expected effectively to improve the Targeting Performance of drug-supplying system.Find more afterwards with the result of corresponding blank micelle through the polymer micelle that the inventive method is made, the variation of its particle size distribution is very small.These results show, the prepared polymer micelle of constant temperature oscillation New Process for Treatment of the present invention not only has the good particle size distribution characteristic that improves the drug targeting performance, and has stable particle size distribution characteristic.
), drug loading and entrapment efficiency determination
(1) measure the chromatographic condition of content of taxol with RP-HPLC method (external standard method)
Chromatographic column: Dikma RP-C 18Post (4.6mm * 200mm, 5 μ m); Mobile phase is acetonitrile-water (55:45), and flow velocity is 1ml/min; The detection wavelength is 227nm, sample size 20 μ l; Column temperature: 25 ℃.
(2) standard curve of drug loading
Precision takes paclitaxel reference substance 32mg, dissolves and is settled to 50ml with acetonitrile, and being mixed with concentration is 640 μ g/ml solution, puts 4 ℃ of Refrigerator stores.With acetonitrile, the paclitaxel standard solution is mixed with respectively the solution that concentration is 64,32,16,8,4,2,1 μ g/ml, by above-mentioned chromatographic condition operation, at the 227nm place, adopt the RP-HPLC method to measure respectively the peak area of paclitaxel, the point that 7 groups of measured results are plotted in Fig. 2 illustrates.As seen from Figure 2, these points have good linear distribution characteristics, and we adopt equation of linear regression to obtain the standard curve of its drug loading like this.Note records the paclitaxel peak area and is YBe designated as with respective concentration XAfter, the equation that obtains of match is as follows
Figure DEST_PATH_IMAGE006
(1)
The correlation coefficient of its match
Figure DEST_PATH_IMAGE008
This result shows, in the concentration range of measuring, the peak area of paclitaxel and the drug loading standard curve between concentration present good line relationship, and then adopts high performance liquid chromatography to determine that the method for paclitaxel concentration is accurately and reliably.
(3) method response rate experiment
At blank PEG 2000Add precision to take appropriate paclitaxel in-DSPE micelle, be mixed with acetonitrile the sample that theoretical concentration is respectively 64,8,1 μ g/ml, adopt the RP-HPLC method to measure respectively their peak area, then to use gained standard curve equation (1) to obtain the drug level value (be working sample value M Paclitaxel-PEG2000-DSPE micelle); Then separately to blank PEG 2000-DSPE micelle is done same concentration determination (being blank value).So the formula of the computational methods response rate is
The response rate (%)=(working sample value-blank value)/addition * 100% (2)
Here addition is theoretical sample concentration.For the paclitaxel of variable concentrations, the method response rate that records the results are shown in Table 2.Show as seen thus, the end value that the paclitaxel method response rate that the inventive method obtains and existing method record is suitable, remains on same index level.Therefore, the present invention's mensuration of carrying out is reliable.
The method response rate of table 2 paclitaxel
Paclitaxel concentration (μ g/ml) The method response rate ( ) (
Figure DEST_PATH_IMAGE012
)
Figure DEST_PATH_IMAGE016
Figure DEST_PATH_IMAGE020
Figure DEST_PATH_IMAGE022
(4) mensuration of drug loading
Be dissolved in the methanol of certain volume taking the paclitaxel polymer micelle that a certain amount of the present embodiment makes, survey peak area with the RP-HPLC method, calculate concentration by standard curve again, the concentration that itself and the aforementioned micelle that contains DSPE is measured compares, and the drug loading calculating formula that just obtains the latter is as follows
Drug loading (%)=(M Paclitaxel)/(M Paclitaxel-PEG2000-DSPE micelle) * 100% (3)
M wherein PaclitaxelBe dissolved in the drug level that records in methanol for the paclitaxel polymer micelle.The measured drug loading of micelle that the inventive method is made is 4.32%, and this result is suitable with the existing methods drug loading.
(5) mensuration of envelop rate
At the micelle that generates with 5ml dissolve with methanol the inventive method, be precipitated material through centrifugalize with after filtering, then survey its peak area with the RP-HPLC method, utilize the standard curve of paclitaxel to obtain its drug level M The paclitaxel dosageAfter, adopt as shown in the formula just obtaining the envelop rate of corresponding micelle, namely
Envelop rate (%)=(M Paclitaxel)/(M The paclitaxel dosage) * 100% (4)
Paclitaxel-the PEG that generates for the inventive method 2000-DSPE polymer micelle, measured envelop rate are 90.1%, and this result than the similar micelle of existing other method preparation has improved 5% left and right.
Embodiment 2
1, the chimeric preparation that the paclitaxel polymer micelle of DSPE is arranged
Consider the dissolubility of DSPE, by choosing the different proportion material composition, prepare different carrier micelles.Namely under the paclitaxel situation of same amount, by choosing not commensurability carrier material PEG 2000-DSPE(9mg, 7mg, 3mg), with chloroform (3ml) dissolving of appropriate volume; Each carrier material quality all remains 10mg, and correspondence is chosen DSPE amount (1mg, 3mg, 7mg) and added the 1ml chloroform so respectively, stirs DSPE is dissolved fully in 65 ℃ of oil baths.Then adopt 1 the preparation method of embodiment 1, obtained the carrier micelle of three kinds of different formulated components.As a comparison, under the paclitaxel situation of same amount, dissolve with the chloroform of 3ml; After the 10mg carrier material is all selected DSPE, through same dissolution mechanism and preparation process, obtained control sample.
2, particle size determination result
Paclitaxel polymer micelle for above-mentioned 1 prepared chimeric DSPE contains more rigid radical in the structure due to DSPE, experiment shows can't form polymer micelle with DSPE merely.That is be entirely DSPE when carrier material, when adopting thin film aquation legal system of the present invention standby, the film of formation is insoluble in 0.9% sodium chloride solution, thereby can't form transparent micellar solution.
Work as PEG 2000After-DSPE part was substituted by DSPE, the inventive method can prepare the paclitaxel polymer micelle of the chimeric DSPE of output, and then can make the cost of this type of drug-supplying system.And contain a certain amount of PEG in the paclitaxel polymer micelle carrier material of this chimeric DSPE 2000During-DSPE, all can obtain micellar solution by preparation method of the present invention.Along with the minimizing with PEG-DSPE of adding of DSPE, the particle diameter of preparation-obtained paclitaxel polymer micelle increases to some extent, and concrete measurement result is listed in table 3.Meanwhile, experimental result shows that also the stability of gained micelle also also increases with this changes of contents.Namely when substitute was increased to 70%, the time of micelle stability surpassed 5 days, the less than over not containing the substitute situation far away 3 days.
The experiment value of the chimeric DSPE paclitaxel of table 3 polymer micelle particle diameter
DSPE and PEG 2000-DSPE mass ratio The mean diameter of experiment measuring
Figure DEST_PATH_IMAGE028
Figure DEST_PATH_IMAGE030
Figure DEST_PATH_IMAGE032
Figure DEST_PATH_IMAGE034
Figure DEST_PATH_IMAGE036
Embodiment 1,2 instrument equipment:
1100 type high performance liquid chromatographs (U.S. Agilent company); Nicomp TM380ZLS type particle size analyzer (U.S. PSS company); RE-52A type rotary evaporator (upper Nereid section Industrial Co., Ltd.); SHZ-III type circulation vacuum pump (upper Nereid section Industrial Co., Ltd.); W201B type thermostat water bath (upper Nereid section Industrial Co., Ltd.); DZF-6050 type vacuum drying oven (upper Nereid section Industrial Co., Ltd.); SHZ-B type water-bath constant temperature oscillator; BP1245 type electronic balance.
：
Paclitaxel (Shanghai Sunve Pharmaceutical Co., Ltd., content 98.6%); PEG 2000-DSPE (German Lipoid company); DSPE (DSPE, German Lipoid company); The paclitaxel reference substance; Chloroform: analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group; Acetonitrile: chromatographically pure, U.S. TEDIA; 0.9% sodium chloride solution (autogamy).
It should be noted that at last: the above only is the preferred embodiments of the present invention, be not limited to the present invention, although with reference to previous embodiment, the present invention is had been described in detail, for a person skilled in the art, it still can be modified to the technical scheme that aforementioned each embodiment puts down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.

Claims (2)

1. preparation process of taxol-polymer medicine-carrying micelles is characterized in that: comprises the steps,
1) mixed liquor of preparation paclitaxel and carrier material;
2) make dried lipid thin film and remove residual organic solvent;
3) in tepidarium, add appropriate 0.9% sodium chloride solution, be placed in water bath with thermostatic control shaker constant temperature oscillation 0.5-5h, frequency is 50-250 time per minute;
4) step 3) gained feed liquid is cooling, membrane filtration namely makes paclitaxel-polymer medicament carrying micelle;
Wherein, described carrier material is PEG 2000The mixture of-DSPE and DSPE, and the mass ratio of DSPE is 10-30%.
2. preparation process of taxol-polymer medicine-carrying micelles according to claim 1 is characterized in that: in described step 3), and constant temperature oscillation 1h, frequency is 150 times per minute.
CN 201110255867 2011-08-31 2011-08-31 Preparation process of taxol-polymer medicine-carrying micelles Expired - Fee Related CN102293736B (en)

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US9974860B2 (en) * 2013-09-13 2018-05-22 Akiko Itai Aqueous solution formulation and method for manufacturing same
CN104174036B (en) * 2014-08-29 2018-03-13 国家纳米科学中心 A kind of nano-micelle for realizing diagnosis and treatment integration and its preparation method and application
CN107365284A (en) * 2017-08-16 2017-11-21 桂林茗兴生物科技有限公司 A kind of method that taxol is extracted from Chinese yew
CN111743877A (en) * 2019-03-28 2020-10-09 复旦大学 Paclitaxel lapatinib compound nanocrystal and preparation method thereof
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