CN105250218A - Micelle preparation for loading docetaxel - Google Patents
Micelle preparation for loading docetaxel Download PDFInfo
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- CN105250218A CN105250218A CN201410336411.8A CN201410336411A CN105250218A CN 105250218 A CN105250218 A CN 105250218A CN 201410336411 A CN201410336411 A CN 201410336411A CN 105250218 A CN105250218 A CN 105250218A
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- docetaxel
- polylactide
- phenylalanine
- micellar preparation
- methoxypolyethylene glycol
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Abstract
The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a micelle preparation for loading docetaxel. According to the present invention, a polyethylene glycol methyl ether-polylactide-phenylalanine triblock copolymer is adopted as a micelle carrier, the micelles formed from the micelle carrier and docetaxel have characteristics of small particle size and high stability, and the preparation does not require the addition of other auxiliary components so as to provide high safety; and the preparation process is simple and is suitable for industrial applications.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, be specifically related to the micellar preparation of a kind of year docetaxel.
Background technology
Docetaxel (Docetaxel, Docetaxel, C
43h
53nO
14), on the architecture basics of natural antitumor drug taxol, a kind of new antitumor drug obtained after structural modification, its anti-spectrum and taxanes are seemingly, mechanism of action promotes tubulin polymerization and stops microtubule depolymerization, thus the mitosis of anticancer and propagation, drug effect is stronger than paclitaxel.
External research shows, at people's mammary gland, colon, bladder and epithelioid cell strain, its IC50 is lower than paclitaxel 9 times.In vivo study shows, docetaxel has high resistance tumor promotion, and after medication, Mus tumor and mouse transplanting tumor can disappear completely.The more important thing is, docetaxel spontaneously can not produce the cross resistance to docetaxel to the cell strain of taxol resistance.
Docetaxel is white or the powder of off-white color, is highly fat-soluble and is insoluble in the medicine of water, and its dissolubility in water is 6-7 μ g/ml.In order to increase its dissolubility, all need in the equal formula of docetaxel injecta commercially available at present to add Tween 80 as surfactant.And adopt Tween 80 to have two large shortcomings.
First shortcoming brings stronger untoward reaction to patient.Tween 80 may cause the untoward reaction comprising anaphylaxis, haemolysis, cardiovascular adverse effects and fluid retention etc.(" tween 80 causes the reason desk study of animal anaphylactoid reaction ", " toxicology magazine " 04 phase in 2007; " pharmacology of pharmaceutic adjuvant Tween 80, pharmacokinetics and analytical method progress ", " Chinese Pharmaceutical Affairs " the 22nd volume the 8th phase in 2008).Therefore need to desensitize to patient's oral glucocorticoid class medicine in advance, to there is anaphylactoid client need Injection of Adrenaline, this has increased the weight of the burden of patient undoubtedly.
Second shortcoming is medication more complicated, adds the difficulty of use.For taxotere: need first to mix concentrated medicine and dilute solution to prepare aqueous premix, then with the normal saline of 0.9%, aqueous premix is diluted, in 4 hours after obtained premixing diluent, the premixing diluent obtained is carried out to the instillation of about 1 hour.Need in this process carefully the concentrated medicine being mixed with dilute solution to be put upside down 45 seconds, and do not stir, bubble may be formed in the solution obtained like this, therefore need this solution left standstill to discharge to make bubble for 5 minutes.Following comment is had: " every bottle of labelled amount is the Docetaxel of 1ml:20mg; the actual 1.2ml of being equipped with concentration is the docetaxel solution of 20mg/ml, is equivalent to the docetaxel of 24mg in the product description of the docetaxel injection " Docetaxel " of Shandong pharmaceutical manufacturing.This volume supplements the loss of liquid that the reason such as the medicinal liquid adhesion bottle wall caused due to medicinal liquid thickness in set-up procedure and " dead volume " that can not extract out causes.During use, with syringe, every bottle of solution extraction is clean and be diluted in 5% glucose injection or 0.9% sodium chloride injection.Toxicity is caused for avoiding overdose.Be sure not to do the wash cillin bottle and syringe with solvent! ".
Polymer micelle is by the spontaneous a kind of nucleocapsid structure formed of amphipathic nature block polymer, has Nano Particle.Polymer micelle was proposed in 1984 by Bader etc. first as a kind of drug administration carrier.Drug encapsulation in the hydrophobic inner core of micelle, is reached the effect that solubilising insoluble drug improves bioavailability further by use amphipathic nature block polymer.In addition, good polymer micelle energy prolong drug circulation time in vivo, reduces drug toxicity, and reaches passive target effect by EPR effect.
Polymer is adopted to make the shortcoming that docetaxel micellar preparation can overcome commercially available docetaxel medicament, but the micelle achievement in research at present for docetaxel generally lacks practical value, main shortcoming comprises particle diameter cannot play EPR effect too greatly, and drug loading is too low, preparation stability is poor.The Yu Kewei of such as Shandong University adopts Pluronic F68 as micellar carrier, VE TPGS does solubilizing agent, docetaxel is wrapped up, the docetaxel micelle drug loading that result obtains only has 0.923%, and mean diameter is up to 135.1 ± 3.42nm (Yu Kewei, " research of docetaxel polymer micelle ").The docetaxel micelle particle diameter that Shandong University Zhang Na etc. utilizes PLA-PEG copolymer to obtain is 144-206nm (" preparation method of polyene-containing taxol nanoparticle mixed micelle preparation and lyophilized preparation ", number of patent application: 201010151501.1).The people such as Shandong University Zhai Guang happiness adopt TPGS, mPEG-PLA, CSO-SA to be that micellar carrier material obtains docetaxel micelle, drug loading is no more than 5.2% " a kind of carrying docetaxel mixed micelle preparation and preparation method thereof ", number of patent application: 201210372072.X).
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, the micellar preparation of a kind of year docetaxel is provided.It adopts methoxypolyethylene glycol-polylactide-phenylalanine as micellar carrier material, form micelle with docetaxel, its particle diameter is less, stability is higher, and without the need to adding other auxiliary elements in preparation, safety is higher, and preparation technology is simply easy to commercial Application.
Technical solution of the present invention is as follows.
A micellar preparation for year docetaxel, adopts methoxypolyethylene glycol-polylactide-phenylalanine triblock copolymer to be micellar carrier; The molecular formula of described methoxypolyethylene glycol-polylactide-phenylalanine is as follows:
Wherein a=10-200, b=3-30.
Preferably, in methoxypolyethylene glycol-polylactide-phenylalanine of the present invention, the mean molecule quantity of methoxypolyethylene glycol block is 998 ~ 2998, and the mean molecule quantity of polylactide block is 502 ~ 4962.The numerical value of different block mean molecule quantity in methoxypolyethylene glycol-polylactide-phenylalanine can be obtained by means such as mass spectral analyses.
The micellar preparation carrying docetaxel in the present invention adopts thin film aquation legal system for obtaining, and comprises the steps: 1. to take docetaxel and methoxypolyethylene glycol-polylactide-phenylalanine according to different rate of charges; 2. above-mentioned raw materials being dropped in container, adding ethanol or acetonitrile to dissolving completely; 3. rotary evaporation 2h at 30-50 DEG C of temperature, to organic solvent distilled-to-dryness, at 10-60 DEG C of temperature, more than vacuum drying 12h removes residual organic solvent, obtains the polymer mixed film containing docetaxel; 4. hybrid films is in 40-60 DEG C of temperature water bath to transparence, and add ultra-pure water or normal saline, the phosphate buffer of identical preheating temperature, shake well aquation, obtains transparent polypeptide drug-loaded micelle solution; 5. by described polypeptide drug-loaded micelle solution 0.45 μm of filtering with microporous membrane, micellar preparation is obtained.
Ethanol residual in above-mentioned micellar preparation or ethane nitrile content are less than 10ppm.
Above-mentionedly state in micellar preparation, the mean diameter of micelle is 18.4 ~ 24.7nm.
In the present invention, described docetaxel refers to anhydrous docetaxel crude drug, according to C
43h
53nO
14meter, purity is more than 98.0%.
In the present invention, research shows, the polyethylene glycol stabilized property of block is very high, is more difficultly degraded; Block polylactide only has just easily degrades under strongly acidic conditions; Grafted amino group acid is reacted in neutral conditions.Therefore methoxypolyethylene glycol-the stability of polylactide-phenylalanine in normal body fluid environment is higher.Methoxypolyethylene glycol-polylactide-phenylalanine is without obvious carcinogenecity, and without genotoxicity, without teratogenesis, mutagenicity, degradable is lactic acid, aminoacid PEG in vivo, all can directly excrete.Acute toxicity test is carried out to mice, the LD50>2.00g/kg of mice; In long term toxication, 1.00g/kg dosage, 1 times/day, successive administration 2 days weekly, drug withdrawal 5 days, successive administration, after 13 weeks, recovers to observe after 4 weeks, has no obvious toxic-side effects.
Cytotoxicity test shows, the cytotoxicity of methoxypolyethylene glycol-polylactide-phenylalanine is lower than the block copolymer mPEG-PLA of current generally recognized as safe (seeing the following form 1).
Table 1MTT method hepatotoxicity test result
Compared with prior art, the present invention has following beneficial effect:
1. methoxypolyethylene glycol-polylactide-the phenylalanine adopting toxicity lower is micellar carrier, and without the need to adding other adjuvants in micellar preparation.Safety is higher.
2. micelle particle diameter is less, and stability is higher.
3. preparation technology is simple, is easy to commercial Application.
Detailed description of the invention
Be described in detail the present invention below in conjunction with embodiment, the present embodiment is implemented under premised on technical solution of the present invention, give detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.Material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
Embodiment (1-7)
Docetaxel is anhydrous docetaxel crude drug (CAS:114977-28-5), is produced by Tian Feng bio tech ltd, Xi'an;
Methoxypolyethylene glycol-polylactide-phenylalanine, is prepared according to the technique described in patent No. PCT-CN-2013000453 voluntarily by inventor.Mass spectral analysis the molecular weight of association reaction raw material is adopted to determine the mean molecule quantity of different block.
A micellar preparation for year docetaxel, can adopt that direct dissolution method, dialysis or thin film aquation legal system are standby to be obtained.In the present embodiment, adopt thin film aquation legal system standby, comprise the following steps.
1. docetaxel and methoxypolyethylene glycol-polylactide-phenylalanine (see table 2) is weighed according to different rate of charges;
2. drop in container by above-mentioned raw materials, add organic solvent to dissolving completely, the kind of organic solvent is selected from any one or several in ethanol, acetonitrile etc.30-50 DEG C of rotary evaporation 2h is to organic solvent distilled-to-dryness, and at 10-60 DEG C, vacuum drying > 12h removes residual organic solvent, obtains the polymer mixed film containing docetaxel.
3. hybrid films is in 40-60 DEG C of water-bath to transparence, and add ultra-pure water or normal saline, the phosphate buffer of identical preheating temperature, shake well aquation, obtains transparent polypeptide drug-loaded micelle solution.
4. by described polypeptide drug-loaded micelle solution 0.45 μm of filtering with microporous membrane, micellar preparation of the present invention is obtained.
Embodiment 1-7 selects different rate of charges respectively, and selects the methoxypolyethylene glycol-polylactide-phenylalanine of different block molecule amount respectively, obtains docetaxel micellar preparation according to above-mentioned steps.Use its drug loading of high-performance liquid chromatogram determination (see table 2).By the particle size distribution of the different embodiment of Dynamic Light Scattering Determination between 10-100nm, mean diameter is (be shown in table 2) between 18.4 ~ 24.7nm.Detect ethanol residual in micellar preparation or ethane nitrile content with gas chromatography, the measurement result of embodiment 1-7 is all less than 10ppm.
The different embodiment of table 2 and actual measurement drug loading
Carrier=methoxypolyethylene glycol-polylactide-phenylalanine
Stability test.The docetaxel micellar preparation dilution obtained by embodiment 1-7 with water obtains the solution that docetaxel concentration is about 3mg/ml, respectively at 15 DEG C, 25 DEG C, 30 DEG C, under normal indoor illumination condition, whether has precipitation or muddy generation every 2h perusal solution.If have precipitation or muddy generation, then illustrate that solution finishes steady statue.Stability test the results are shown in Table 3.
Table 3 different embodiment stability test result
Claims (6)
1. carry a micellar preparation for docetaxel, it is characterized in that, adopt methoxypolyethylene glycol-polylactide-phenylalanine triblock copolymer to be micellar carrier; The molecular formula of described methoxypolyethylene glycol-polylactide-phenylalanine is as follows:
Wherein a=10-200, b=3-30.
2. the micellar preparation of according to claim 1 year docetaxel, is characterized in that: in described methoxypolyethylene glycol-polylactide-phenylalanine, and the mean molecule quantity of polylactide block is 502 ~ 4962.
3. the micellar preparation of according to claim 1 year docetaxel, is characterized in that: in described methoxypolyethylene glycol-polylactide-phenylalanine, and the mean molecule quantity of methoxypolyethylene glycol block is 998 ~ 2998.
4. according to the micellar preparation carrying docetaxel one of claim 1-3 Suo Shu, it is characterized in that: adopting thin film aquation legal system for obtaining, comprising the steps: 1. to take docetaxel and methoxypolyethylene glycol-polylactide-phenylalanine according to different rate of charges; 2. above-mentioned raw materials being dropped in container, adding ethanol or acetonitrile to dissolving completely; 3. at 30-50 DEG C of temperature, rotary evaporation 2h is to organic solvent distilled-to-dryness, then at 10-60 DEG C, more than vacuum drying 12h removes residual organic solvent, obtains the polymer mixed film containing docetaxel; 4. hybrid films is in 40-60 DEG C of temperature water bath to transparence, and add ultra-pure water or normal saline, the phosphate buffer of identical preheating temperature, shake well aquation, obtains transparent polypeptide drug-loaded micelle solution; 5. by described polypeptide drug-loaded micelle solution 0.45 μm of filtering with microporous membrane, micellar preparation is obtained.
5. the micellar preparation of according to claim 4 year docetaxel, is characterized in that: in described micellar preparation, and residual ethanol or ethane nitrile content are less than 10ppm.
6. the micellar preparation of according to claim 5 year docetaxel, is characterized in that: in described micellar preparation, and the mean diameter of micelle is 18.4 ~ 24.7nm.
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| CN201410336411.8A CN105250218A (en) | 2014-07-15 | 2014-07-15 | Micelle preparation for loading docetaxel |
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| CN201410336411.8A CN105250218A (en) | 2014-07-15 | 2014-07-15 | Micelle preparation for loading docetaxel |
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Cited By (2)
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| CN111819217A (en) * | 2018-02-13 | 2020-10-23 | 上海时莱生物技术有限公司 | Amphiphilic block copolymer, preparation method thereof and nano micelle drug loading system |
| CN112972375A (en) * | 2021-02-06 | 2021-06-18 | 绍兴文理学院 | 2- (4-chloro-phenoxymethyl) -4- (N-isobutyl-N-piperonyl-aminomethyl) -thiazole micelles |
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| CN102617843A (en) * | 2012-04-09 | 2012-08-01 | 福州市台江区泽越医药技术有限公司 | Preparation of biomedical amino acid-polyether-polyester triblock copolymer |
| CN103772686A (en) * | 2012-10-26 | 2014-05-07 | 苏州雷纳药物研发有限公司 | Amphiphilic block copolymer and preparation method thereof, micelle drug delivery system formed by copolymer and anti-tumor drug |
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2014
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011011978A1 (en) * | 2009-07-31 | 2011-02-03 | 西安力邦医药科技有限责任公司 | Nanosphere or microsphere drug carrier, preparation method, composition and use thereof |
| CN102617843A (en) * | 2012-04-09 | 2012-08-01 | 福州市台江区泽越医药技术有限公司 | Preparation of biomedical amino acid-polyether-polyester triblock copolymer |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111819217A (en) * | 2018-02-13 | 2020-10-23 | 上海时莱生物技术有限公司 | Amphiphilic block copolymer, preparation method thereof and nano micelle drug loading system |
| CN111819217B (en) * | 2018-02-13 | 2021-10-01 | 张富尧 | Amphiphilic block copolymer, preparation method thereof and nano micelle drug loading system |
| CN112972375A (en) * | 2021-02-06 | 2021-06-18 | 绍兴文理学院 | 2- (4-chloro-phenoxymethyl) -4- (N-isobutyl-N-piperonyl-aminomethyl) -thiazole micelles |
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