CN109432001A - The production technology and its product of taxol micellar preparation - Google Patents
The production technology and its product of taxol micellar preparation Download PDFInfo
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- CN109432001A CN109432001A CN201811576589.4A CN201811576589A CN109432001A CN 109432001 A CN109432001 A CN 109432001A CN 201811576589 A CN201811576589 A CN 201811576589A CN 109432001 A CN109432001 A CN 109432001A
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- taxol
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- micellar preparation
- phenylalanine
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Abstract
The invention belongs to pharmaceutical preparations technology fields, the specially production technology and its product of taxol glue preparation.It uses mPEG-PLA- phenylalanine triblock copolymer for micellar carrier.The average grain diameter of taxol micella is 21 ~ 35nm.It is prepared by direct dissolution method, dialysis or film hydration method.The beneficial effects of the present invention are: use the lower methoxypolyethylene glycol-polylactide-phenylalanine of toxicity for micellar carrier, and without adding other auxiliary materials in micellar preparation, safety is higher；Vitro stability is higher, and it is more than 12 hours that taxol micella keeps the stable time at room temperature, and stability is more than 168 hours under low temperature；Blood stability is higher, and partial size is smaller, is easier to play ERP effect.
Description
Technical field
The invention belongs to pharmaceutical preparations technology fields, and in particular to the production technology and its product of taxol glue preparation.
Background technique
Taxane molecule formula are as follows: C47H51NO14, molecular weight 853.9, has highly lipophilic property by 213 ~ 216 DEG C of fusing point, insoluble
Yu Shui is the natural anti-cancer drugs of a kind of efficient, low toxicity isolated from Chinese yew genus plants at first, wide spectrum.It is red
The natural secondary metabolin of one of beans genus Taxus complexity, molecular structure are as follows.
Taxol is the drug of a kind of micro-pipe specificity having compared with high anti-cancer activity, and sales volume ranks anti-cancer agent throughout the year
The umber one, and with 20% speed increase.
1977, Horwit Z discovery taxol anticancer mechanism was that tubulin can be promoted with tubulin binding
Polymerization is assembled into micro-pipe dimer, to inhibit the normal physiological depolymerization of micro-pipe in cell, cell mitogen is made to stop at G2
Phase and M phase prevent the quick breeding of cancer cell.Further study show that taxol can activating macrophage, lead to tumour
The reduction and its release of mecrosis factor receptors, killing or inhibition tumour cell；Taxol can induce cell apoptosis, and cause cell
Programmed death；Taxol can also inhibit the migration of tumour cell.Clinical research shows that taxol has wide spectrum and efficiently resists
Cancer activity, prominent for treatment oophoroma, breast cancer, uterine cancer, gastric cancer etc. curative effect, recent research finds it to rheumatoid
Property arthritis, senile dementia etc. also have certain curative effect.
Since taxol is insoluble in water, taxol is usually dissolved in Emulsifier EL-60 in current clinical application
To increase its water solubility in (cremophor EL) and dehydrated alcohol mixed solvent.But ethyl alcohol has certain cytotoxicity, and
Histamine is discharged when Emulsifier EL-60 degradation in vivo, leads to different degrees of allergic reaction, can also be caused in nerve cell
Particle release and disentwining angle velocity and aggravate the peripheral nerve toxicity of taxol.
Its curative effect is improved to reduce the toxicity of formulation for paclitaxel, clinically develops the new agent of taxol successively in recent years
Type.Wherein at home and abroad listed without Emulsifier EL-60 injection taxol albumin nano suspension (ABI-007).Tool
There is the features such as not having to antiallergy pretreatment, curative effect is preferable, toxicity is lower；The purple of clinical research China research and development is now just carried out at home
China fir alcohol liposome started in clinical application and the pro-drug (DHA-PTX) and polymeric dosage form genexol-PM of taxol and
Xyotax is also just in the research of preclinical and clinical I-III phase, it is shown that good prospect.
But recent study is found, the biggish polymer micelle of the partial size either formed by heavy polymer, also
It is the lesser polymer micelle of partial size formed by low-molecular weight polymer, has the shortcomings that blood stability is poor, micella exists
Almost immediately disintegrate and discharge the drug of carrying after into blood, the distribution of the drug that final two kinds of micellas carry in vivo is almost
It is not different, does not show ERP effect.Savic R's et al. the study found that taxol micella enters after blood usually 5
90% drug release is just had more than in minute and toward tissue diffusion (see Langmuir 2006,22:3570-8. " Assessment
of the integrity of poly (caprolactone)-b-poly(ethylene oxide) micelles under
Biological conditions:a fl uorogenic-based approach. ").
This result and imagination are reached tumor locus and are passed through EPR effect release drug again by micella particle carrying drug
Perfect condition greatly differs from each other, i.e., non-mature release (Premature release).The reason of being directed at non-mature release on the one hand by
Micella is caused to disintegrate lower than its critical micelle concentration (CMC concentration) in concentration of the micella after hemodilution, another aspect blood
A large amount of existing protein can have an effect with micella and cause it to reunite and discharge drug in liquid.Therefore, it is injected intravenously in design
Its blood stability must be considered when cancer target nano-carrier first, is only just expected under the premise of improving blood stability
The targeting of drug is improved using EPR effect.
Another of existing taxol micella is disadvantageous in that process conditions are more complex, increases to heavy industrialization
Difficulty.For example, preparation process of taxol-polymer medicine-carrying micelles (the number of patent application of Lanzhou University Liu Weisheng et al. invention
201110255867.8) need process conditions using constant temperature oscillation；A kind of taxol of Peking University Lv Wanliang et al. invention
Nano-micelle and its application (application number: 201110044677.1) need to keep reaction environment using buffer during the preparation process
PH value stablize.Contain a certain amount of ethyl alcohol in taxol micella also, still there is certain cytotoxicity.Such as Shandong
Li Lingbing of university et al. has invented a kind of taxol mixed micelle preparation and preparation method thereof (number of patent application
201110139712.8), but still contain ethyl alcohol in its mixed micelle.
Summary of the invention
The present invention is described in detail below with reference to embodiment, the present embodiment is under the premise of the technical scheme of the present invention
Implemented, the detailed implementation method and specific operation process are given, but protection scope of the present invention be not limited to it is following
Embodiment.The materials, reagents and the like used in the following examples obtains from commercial channels unless otherwise specified.
Embodiment (1-7)
The production technology of taxol micellar preparation can be obtained using direct dissolution method, dialysis or film hydration method.It is preferred that
, it is obtained, is included the following steps using film hydration method.
1, raw material is weighed according to the taxol feed ratio (see Table 1) different from mPEG-PLA- phenylalanine.Wherein, raw material
Taxol (CAS 33069-62-4) is produced by Xi'an Rayleigh Biotechnology Co., Ltd, and purity is greater than 95%, mPEG-PLA- benzene
Alanine is voluntarily prepared as inventor according to technique described in patent No. PCT-CN-2013000453；
2, above-mentioned raw materials are put into container, the organic solvents such as ethyl alcohol or acetonitrile are added to being completely dissolved.30-50 DEG C of rotary evaporation
2h is to organic solvent distilled-to-dryness, and vacuum drying > 12h removes remaining organic solvent at 10-60 DEG C, obtains containing taxol
Mixed with polymers film；
3, for hybrid films in 40-60 DEG C of water-bath to transparence, ultrapure water or physiological saline, the phosphate that identical preheating temperature is added are slow
Fliud flushing, shake well aquation obtain transparent polypeptide drug-loaded micelle solution；
4, by 0.45 μm of filtering with microporous membrane of the polypeptide drug-loaded micelle solution.
Embodiment 1-7 selects different feed ratios respectively, and selects the mPEG-PLA- benzene of different block molecule amounts respectively
Taxol micellar preparation is made according to above-mentioned steps in alanine.With high effective liquid chromatography for measuring drugloading rate.Use dynamic light scattering
Partial size is measured, measures particle diameter distribution between 10-100nm, average grain diameter (see Table 1) between 20.8-35.2nm.
Table 1: the drugloading rate and partial size of different embodiments
Carrier=mPEG-PLA- phenylalanine
The measuring method of micellar solution stability is to dilute polypeptide drug-loaded micelle solution with sterile water, and obtaining paclitaxel concentration is about
The solution of 3mg/ml is transferred in ampoule bottle in an aseptic environment and seals.Respectively at 4 DEG C, 15 DEG C, 25 DEG C, normal indoor light
According under the conditions of, visually observe whether the solution in ampoule bottle has precipitating or muddy generation every 2h.If there is precipitating or muddiness
It generates, then illustrates that solution finishes stable state.It the results are shown in Table 2.
Paclitaxel injection is extremely unstable, and device need to have filtering function used in the process of instillation, and drug is prevented to be precipitated, and
Taxol micella high stability, instillation are not required to filter device.
Table 2: stability test result
The blood stability of the comparison present invention and mpeg-pla taxol micella.It is 3mg/ that the present invention, which is diluted to content of taxol,
The blood plasma of 50wt% is added after ml；Control group uses the mpeg-pla taxol micella of same paclitaxel concentration, same to be added
The blood plasma of 50wt%.Every 1 hour with dynamic light scattering measurement particle diameter distribution coefficient (PDI) whether > 0.3, as a result such as table 3.This when
Between shorter its stability in blood plasma of explanation it is poorer, illustrate that blood of the invention stablizes the time and is significantly higher than mpeg-pla Japanese yew
Alcohol micella.
Table 3: blood stability test result
Claims (6)
1. the production technology of taxol micellar preparation, which is characterized in that use mPEG-PLA- phenylalanine triblock copolymer for
Micellar carrier, the mPEG-PLA- phenylalanine triblock copolymer molecular formula are as follows
Wherein, a=11-455, b=3-300.
2. the production technology of taxol micellar preparation according to claim 1, it is characterised in that: the mPEG-PLA-
In phenylalanine, the molecular weight of methoxypolyethylene glycol block is 1000 ~ 3000.
3. the production technology of taxol micellar preparation according to claim 1, it is characterised in that: the mPEG-PLA-
In phenylalanine, the molecular weight of polylactide block is 500 ~ 5000.
4. the production technology of taxol micellar preparation according to claim 1, it is characterised in that: include the following steps,
Raw material is weighed according to the feed ratio of taxol and mPEG-PLA- phenylalanine；Weighed raw material is put into container, is added
The organic solvents such as ethyl alcohol or acetonitrile are to being completely dissolved；30-50 DEG C of rotary evaporation 2h is to organic solvent distilled-to-dryness, at 10-60 DEG C
It is dried in vacuo 12h or more, remaining organic solvent is removed, obtains the mixed with polymers film containing taxol；Hybrid films are in 40-60 DEG C
To transparence, the ultrapure water or physiological saline or phosphate buffer, shake well aquation that identical preheating temperature is added are obtained for water-bath
Transparent polypeptide drug-loaded micelle solution；By 0.45 μm of filtering with microporous membrane of the polypeptide drug-loaded micelle solution.
5. the production technology of taxol micellar preparation according to claim 1 taxol micellar preparation produced, special
Sign is: remaining ethyl alcohol or ethane nitrile content are less than 10ppm in the taxol micellar preparation.
6. the production technology of taxol micellar preparation according to claim 1 taxol micellar preparation produced, special
Sign is: the average grain diameter of taxol micella is 20.8 ~ 35.2nm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811576589.4A CN109432001A (en) | 2014-05-10 | 2014-05-10 | The production technology and its product of taxol micellar preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811576589.4A CN109432001A (en) | 2014-05-10 | 2014-05-10 | The production technology and its product of taxol micellar preparation |
| CN201410198521.2A CN104546708A (en) | 2014-05-10 | 2014-05-10 | Taxol micelle preparation |
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| CN201410198521.2A Division CN104546708A (en) | 2014-05-10 | 2014-05-10 | Taxol micelle preparation |
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| CN201811576589.4A Pending CN109432001A (en) | 2014-05-10 | 2014-05-10 | The production technology and its product of taxol micellar preparation |
| CN201410198521.2A Pending CN104546708A (en) | 2014-05-10 | 2014-05-10 | Taxol micelle preparation |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP6235755B2 (en) | 2014-07-02 | 2017-11-22 | ザ リサーチ ファウンデイション フォー ザ ステイト ユニバーシティー オブ ニューヨーク | Surfactant-removed micelle composition having a high cargo to surfactant ratio |
| GB2542092B (en) * | 2014-07-15 | 2019-05-29 | Teng Xin | Polyethylene glycol methyl ether-polylactide-lysine micellar compositions comprising docetaxel |
| CN106361697B (en) * | 2016-08-26 | 2019-06-07 | 四川兴康脉通医疗器械有限公司 | A kind of load taxol micellar copolymerization object, preparation and preparation method containing brufen |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516553A (en) * | 2011-11-18 | 2012-06-27 | 上海珀理玫化学科技有限公司 | Method for preparing hydrophilic polyurethane with numerous hydroxyls on side chains |
| CN103342788A (en) * | 2013-06-09 | 2013-10-09 | 中国科学院上海药物研究所 | Triblock polycation, and preparation method and application thereof |
| CN103374128A (en) * | 2012-04-28 | 2013-10-30 | 中国科学院深圳先进技术研究院 | Amphiphilic triblock copolymer, polymer nano-carrier preparation and preparation methods |
| CN103768013A (en) * | 2014-01-17 | 2014-05-07 | 丽珠医药集团股份有限公司 | Paclitaxel polymer micelle by using refined amphiphilic block copolymer as carrier |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005040247A1 (en) * | 2003-10-24 | 2005-05-06 | Samyang Corporation | Polymeric composition for drug delivery |
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- 2014-05-10 CN CN201811576589.4A patent/CN109432001A/en active Pending
- 2014-05-10 CN CN201410198521.2A patent/CN104546708A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516553A (en) * | 2011-11-18 | 2012-06-27 | 上海珀理玫化学科技有限公司 | Method for preparing hydrophilic polyurethane with numerous hydroxyls on side chains |
| CN103374128A (en) * | 2012-04-28 | 2013-10-30 | 中国科学院深圳先进技术研究院 | Amphiphilic triblock copolymer, polymer nano-carrier preparation and preparation methods |
| 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 |
| CN103342788A (en) * | 2013-06-09 | 2013-10-09 | 中国科学院上海药物研究所 | Triblock polycation, and preparation method and application thereof |
| CN103768013A (en) * | 2014-01-17 | 2014-05-07 | 丽珠医药集团股份有限公司 | Paclitaxel polymer micelle by using refined amphiphilic block copolymer as carrier |
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