CN1561987A - Nano micro ball with taxol capable of biologically degradating high molecule and its preparing method - Google Patents
Nano micro ball with taxol capable of biologically degradating high molecule and its preparing method Download PDFInfo
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- CN1561987A CN1561987A CNA200410010733XA CN200410010733A CN1561987A CN 1561987 A CN1561987 A CN 1561987A CN A200410010733X A CNA200410010733X A CN A200410010733XA CN 200410010733 A CN200410010733 A CN 200410010733A CN 1561987 A CN1561987 A CN 1561987A
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Abstract
A biodegradable high-molecular nanoball is prepared from the block copolymer of polylactone and polyethanediol and taxusol through dissolving them in organic solvent, adding the solution to the aqueous solution of polyvinyl alcohol or gelatin, ultrasonic emulsifying, and vacuum volatilization of organic solvent.
Description
Technical field
The invention belongs to the Biodegradable high-molecular Nano microsphere and the preparation method that are loaded with paclitaxel.
Background technology
Paclitaxel is the diterpenoids natural product, be to separate from Pacific yew tree, yewtree (Taxus brevifolia) bark in 1971 and obtain (" JACS " (J.AM.Chem.Soc.) at first by people such as Wani, 93:2325 (1971)), and with chemistry and X-ray crystallography method determined its structure.Found that it is effective to the treatment kinds of tumors, as ovarian cancer, breast carcinoma, nonsmall-cell lung cancer, a cancer and neck cancer etc.
The biological activity of paclitaxel is relevant with the splitted effect of its pair cell, it can promote the microtubule dimer to be assembled into microtubule during cell division, thereafter by stoping the multimerization process to make the stable enhancing of microtubule, thereby suppress the normal kinetics reorganization of microtubule net, and then influence cell vital stage and splitting function.Paclitaxel also can cause the multiple aster generation of microtubule during the unusual and cell division of the arrangement of whole cell cycle microtubule fasolculus.Generally be exactly to suppress growth of tumour cell.It has the effect of the body's immunity of adjusting in addition.The mechanism of paclitaxel is unique, because it is to promote other cancer therapy drug of formation (such as vincaleucoblastine and Colchicine) of microtubule polymerization body then to hinder the formation of microtubule.
The chemical constitution of paclitaxel has high fat, is dissolvable in water organic solvent and water insoluble, and its dissolubility in water is used for the formulation for paclitaxel (Taxol of chemotherapy now less than 0.3mg/ml
) be that paclitaxel is dissolved in polyoxyethylene castor oil (Cremphor
EL) with 1: 1 mixed liquor of dehydrated alcohol in, concentration is 7mmol/l.Releasing rare with 0.9% normal saline or 5% glucose solution before the medication is 0.35～1.4mmol/l to final concentration.
Though existing formulation for paclitaxel has obtained using widely, but still exist a lot of not enough.Maximum shortcoming is exactly owing to use polyoxyethylene castor oil to make the severe allergic reaction that solvent causes, comprises vasodilation, dyspnea and hypotension, in the time of seriously even cause death.Next is that the vein loading equipment made from polrvinyl chloride is incompatible, because it can be dissolved out the plasticizer phthalic acid diethylhexyl ester (DEHP) in the polrvinyl chloride tube for transfusion, makes medicinal liquid become muddy.The DEHP that is dissolved out enters human body, can cause toxicity, because animal experiment shows that DEHP can cause the hepatotoxicity of animal, and makes rodent carcinogenic.In addition, although said preparation before dilution under air-proof condition 4 ℃ keep never degenerating in 5 years, the dilution rear stability is very poor, can only keep several hrs, just has granule to separate out after 24 hours, uses after filtering, drug effect significantly reduces.
Because the poorly water-soluble of paclitaxel, and there are a lot of problems in existing formulation for paclitaxel, thereby the paclitaxel novel formulation that development has a good aqueous solubility is the focus that people study always.In order to improve the therapeutic effect of paclitaxel, solve the side-effect problem that exists in the existing paclitaxel administering mode, people have explored multiple taxol drug induction system, as the liposome, macromole conjugate drug-supplying system, polymer microcapsule etc. of preparation paclitaxel.
In recent years, along with the biodegradation high score development, particularly their excellent biological compatibility and the biodegradable absorbability of research, make it obtain widely to use in medical field.Aspect delivery system, the microsphere that carries the paclitaxel preparation with the biodegradable polymer bag is one of focus of current formulation for paclitaxel research.This type of microsphere capsule is used for the controlled transmission of cancer therapy drug, has medicament curative effect enhancement, reduces the advantage of toxicity.And the high molecular nanometer capsule has unique and excellent more performance.Result of study proves: during the oral administration nanometer microsphere, the nanoscale microsphere can be in intestinal enters into blood and lymphatic systems by mucosa by the tip of intestinal villi, and medicine directly enters blood like this, raising evident in efficacy.
Summary of the invention
The purpose of this invention is to provide a kind of Biodegradable high-molecular Nano microsphere that is loaded with paclitaxel;
Another object of the present invention provides a kind of preparation method that is loaded with the Biodegradable high-molecular Nano microsphere of paclitaxel.
The following (see figure 1) of preparation method that is enclosed with the Biodegradable high-molecular Nano microsphere of paclitaxel of the present invention:
(1) biological degradation polyalcohol is dissolved with dichloromethane, make the solution that concentration is 5～100mg/ml;
(2) paclitaxel is dissolved in the above-mentioned polymer solution, concentration is 1～10mg/ml;
(3) above-mentioned organic solution is joined contain stabilizing agent polyvinyl alcohol or gelatin, mass concentration is that the volume ratio of organic solution and aqueous solution is 1: 20～1: 5, and this mixed liquor is carried out emulsifying in 1～10% the aqueous solution;
(4) above-mentioned emulsion 5～20 times of volumes of distilled water diluting, vacuum volatilization is 2 hours then;
(5) adopt the high speed centrifugation separation method, 5000～20,000rpm collects Nano microsphere down, uses distilled water wash, removes the residual stable agent, and lyophilization again obtains pressed powder.
Above-mentionedly carrying out emulsive method, can be normally used high speed machine stirring and emulsifying, also can be ultrasonic emulsification.The latter is simple to operate, and is convenient and easy, and processing capacity is bigger.Use the ultrasonic emulsification instrument of selling on the market, suitably regulate emulsive power and time, just can realize emulsifying, obtain the needed nanometer particle size and the uniformity.Emulsive concrete operations condition is, paclitaxel and block copolymer are dissolved in the dichloromethane, and in the polyvinyl alcohol water solution that dichloromethane solution is joined, ultrasonic emulsification 40-120 second, emulsifying power is 30-90W.Gained emulsion distilled water diluting, decompression was volatilized 2-4 hour then, and high speed centrifugation is collected Nano microsphere, and the reuse distilled water wash is distributed in the water several times again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
The present invention has carried out following improvement to common oil-in-water (O/W) emulsion method: the firstth, after obtaining the O/W emulsion, dilute with the aqueous solution that contains stabilizing agent.So just reduce the chance that nanoparticle uncured in the organic solvent volatilization process runs foul of each other and condenses, reduced the formation of big particle diameter microsphere; Next is the organic solvent that volatilizees under decompression room temperature, has replaced common evaporable at normal temperatures and pressures way.Do like this and accelerated the solidified speed of nanoparticle, help nanoparticle and form.
The prepared Nano microsphere of the present invention is solid construction, and along with preparation condition changes, particle diameter can be regulated between 300nm～800nm, and drug loading can reach 10～20%.
Polymer used in the present invention is the block copolymer of polyester and Polyethylene Glycol, comprises the copolymer of polylactide, polycaprolactone, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(lactide-caprolactone) and Polyethylene Glycol.They both can be bi-block copolymers, can be again triblock copolymers, and wherein the molecular weight of Polyethylene Glycol block is 500～5000, and the molecular weight of aliphatic polyester section is 10,000～150,000.Above as the aliphatic polyester of medicine parcel carrier and the block copolymer of Polyethylene Glycol, not only has biodegradability, and because the introducing of Polyethylene Glycol, improved the compatibility widely with blood, reduced immunogenicity, during as drug carrier material, but prolong drug circulation time has in vivo improved drug effect.The aliphatic polyester that the present invention uses and the block copolymer of Polyethylene Glycol all are high-molecular weight, its molecular weight ranges is 14,000-160,000, prepared Nano microsphere is together by the micellar phase ratio of low-molecular-weight amphipathic polyester with the block copolymer preparation of Polyethylene Glycol, not only have more micellar advantages,, and can avoid the drug leakage phenomenon that occurs in the micelle medicine carrying delivery system as biocompatibility and long circulation time.The molecular weight of employed Polyethylene Glycol block is in 300～5000 scopes, so that after the aliphatic polyester degraded, they can excrete by kidney.
The formulation for paclitaxel of the Nano microsphere type that the present invention is prepared has advantage easy to use, that dosage is little, toxicity is little, side effect is little.
The paclitaxel rate of release of the Nano capsule that the present invention is prepared can change high molecular molecular weight by changing the kind of macromolecular material, changes particle diameter and regulates.See the following examples for details.
Description of drawings
Fig. 1: preparation technology's flow chart of Nano microsphere: paclitaxel and block copolymer are dissolved in the dichloromethane, in 2% polyvinyl alcohol water solution that dichloromethane solution is joined, ultrasonic emulsification obtains the O/W emulsion, gained emulsion distilled water diluting, decompression volatilization 2-4 hour obtains solidified Nano microsphere then, high speed centrifugation is collected Nano microsphere, the reuse distilled water wash is distributed in the water several times again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
Fig. 2: the electromicroscopic photograph of Nano microsphere.
Fig. 3: the paclitaxel release in vitro behavior contrast figure of the Nano microsphere of the polylactide of usefulness different molecular weight-Polyethylene Glycol di-block copolymer preparation.(a) polylactide 10000-Polyethylene Glycol 5000; (b) polylactide 30000-Polyethylene Glycol 5000; (c) polylactide 60000-Polyethylene Glycol 5000.
Give further instruction below by embodiment to the preparation method that contains the Biodegradable high-molecular Nano microsphere of paclitaxel provided by the invention, but it does not limit the present invention, scope of the present invention is defined by the claims.
The specific embodiment
Embodiment 1
15mg paclitaxel and 85mg polylactide-Polyethylene Glycol di-block copolymer, two block molecule amounts are respectively 60,000 and 5000 and are dissolved in the 5ml dichloromethane, dichloromethane solution are joined in the poly-vinyl alcohol solution of 40ml2%, ultrasonic emulsification 90 seconds, emulsifying power are 70W.Then the gained emulsion is arrived 500ml with distilled water diluting, decompression volatilization 2 hours, 18,000rpm collects Nano microsphere down, and reuse distilled water wash four times is distributed in the water again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
Gained is enclosed with the electromicroscopic photograph of the Nano microsphere of paclitaxel and sees Fig. 2 (a), and its particle diameter is 760 ± 35nm, and drug loading is 12.5% (w/w), and Fig. 3 (a) line is seen in its paclitaxel release in vitro behavior.
Embodiment 2
10mg paclitaxel and 67mg polylactide-Polyethylene Glycol diblock copolymer, two block molecule amounts are respectively 30,000 and 5000 and are dissolved in the 4ml dichloromethane, dichloromethane solution are joined in the poly-vinyl alcohol solution of 40ml2%, ultrasonic emulsification 75 seconds, emulsifying power are 60W.Then the gained emulsion is arrived 400ml with distilled water diluting, decompression volatilization 2 hours, 20,000rpm collects Nano microsphere down, and reuse distilled water wash four times is distributed in the water again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
Gained is enclosed with the electromicroscopic photograph of the Nano microsphere of paclitaxel and sees Fig. 2 (b), and its particle diameter is 520 ± 42nm, and drug loading is 11.4% (w/w), and Fig. 3 (b) line is seen in the paclitaxel release in vitro behavior of microsphere.
Embodiment 3
8mg paclitaxel and 53mg polylactide-Polyethylene Glycol diblock copolymer, two block molecule amounts are respectively 10,000 and 5000 and are dissolved in the 3ml dichloromethane, dichloromethane solution are joined in the poly-vinyl alcohol solution of 40ml 2%, ultrasonic emulsification 60 seconds, emulsifying power are 40W.Then the gained emulsion is arrived 400ml with distilled water diluting, decompression volatilization 2 hours, 20,000rpm collects Nano microsphere down, and reuse distilled water wash four times is distributed in the water again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
Gained is enclosed with the electromicroscopic photograph of the Nano microsphere of paclitaxel and sees Fig. 2 (c), and its particle diameter is 340 ± 50nm, and drug loading is 9.8% (w/w), and Fig. 3 (c) line is seen in the paclitaxel release in vitro behavior of microsphere.
More than among 3 embodiment, the particle diameter of the Nano microsphere that the polylactide of different molecular weight-Polyethylene Glycol di-block copolymer is prepared, encapsulation ratio and drug loading data are collected in the table 1.
Table 1 is loaded with particle diameter, encapsulation ratio and the drug loading of the Nano microsphere of paclitaxel
| Sequence number | Block polymer and molecular weight | Content of taxol (%) | Encapsulation ratio (%) | Particle diameter (nm) | |
| In the batching | In the product | ||||
| 1 | MPEG5000-PLA60000 | ????15 | ????12.5 | ????83.2 | ????760±35 |
| 2 | MPEG5000-PLA30000 | ????15 | ????11.4 | ????76.2 | ????520±42 |
| 3 | MPEG5000-PLA10000 | ????15 | ????9.8 | ????65.5 | ????340±50 |
As seen, parcel uses the molecular weight of polylactic acid section in the polymer to the diameter of nanoparticle and the encapsulation ratio of medicine, has tangible influence.By regulating the length of polylactic acid section, can control these performance indications of Nano microsphere, thus the rate of release of control paclitaxel.
Embodiment 4
10mg paclitaxel and 50mg polycaprolactone-polyethylene glycol diblock copolymer, diblock molecular weight are respectively 40,000 and 2000 and are dissolved in the 5ml dichloromethane, this solution joined in the gelatin solution of 40ml 5%, and ultrasonic emulsification 60 seconds, emulsifying power is 50W.Then the gained emulsion is arrived 400ml with distilled water diluting, decompression volatilization 2 hours, 18,000rpm collects Nano microsphere down, and reuse distilled water wash four times is distributed in the water again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
Embodiment 5
Poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester)-Polyethylene Glycol di-block copolymer diblock molecular weight of 12mg paclitaxel and 60mg is respectively 10,000 and 2000, wherein poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) contains lactide 80%, Acetic acid, hydroxy-, bimol. cyclic ester 20%) be dissolved in the 4ml dichloromethane, this solution is joined in the poly-vinyl alcohol solution of 40ml 2%, ultrasonic emulsification 50 seconds, emulsifying power 50W.Then the gained emulsion is arrived 400ml with distilled water diluting, decompression volatilization 2 hours, 20,000rpm collects Nano microsphere down, and reuse distilled water wash four times is distributed in the water again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
Embodiment 6
15mg paclitaxel and 70mg PLA-PEG-PLA triblock copolymer, three block molecule amounts are respectively 50,000,5000 and 50,000 is dissolved in the 5ml dichloromethane, dichloromethane solution is joined in the poly-vinyl alcohol solution of 40ml 2%, ultrasonic emulsification 80 seconds, emulsifying power are 70W.Then the gained emulsion is arrived 400ml with distilled water diluting, decompression volatilization 2 hours, 18,000rpm collects Nano microsphere down, and reuse distilled water wash four times is distributed in the water again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
Embodiment 7
20mg paclitaxel and 70mg polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer, three block molecule amounts are respectively 30,000,5000 and 30,000 is dissolved in the 4ml dichloromethane, dichloromethane solution is joined in the gelatin solution of 40ml 5%, ultrasonic emulsification 60 seconds, emulsifying power are 60W.Then the gained emulsion is arrived 400ml with distilled water diluting, decompression volatilization 2 hours, 20,000rpm collects Nano microsphere down, and reuse distilled water wash four times is distributed in the water again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
Embodiment 8
15mg paclitaxel and 60mg polycaprolactone-polyethylene glycol-polycaprolactone triblock copolymer, three block molecule amounts are respectively 50,000,5000 and 50,000 is dissolved in the 5ml dichloromethane, dichloromethane solution is joined in the gelatin solution of 40ml 5%, homogenizer emulsifying 1 minute, mixing speed 10,000rpm.Then the gained emulsion is arrived 400ml with distilled water diluting, decompression volatilization 2 hours, 20,000rpm collects Nano microsphere down, and reuse distilled water wash four times is distributed in the water again, and lyophilization obtains containing the Nano microsphere of paclitaxel.
Claims (6)
1, a kind of Biodegradable high-molecular Nano microsphere that is loaded with paclitaxel, wherein Biodegradable high-molecular is the block copolymer of aliphatic polyester and Polyethylene Glycol, mass percent is 80-90%, and the mass percent of paclitaxel is 10-20%, mean particle dia scope 200-1000 nanometer.
2, the described Biodegradable high-molecular Nano microsphere of claim 1, it is characterized in that described Biodegradable high-molecular is the diblock polymer or the triblock copolymer of aliphatic polyester and Polyethylene Glycol, the molecular weight of Polyethylene Glycol block is 500～5000, and the molecular weight of aliphatic polyester section is 10000～150000.
3, the described Biodegradable high-molecular Nano microsphere of claim 1, the aliphatic polyester block that it is characterized in that used block copolymer are polylactide, polycaprolactone, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester) or poly-(lactide-caprolactone).
4, the preparation method of the described Biodegradable high-molecular Nano microsphere of claim 1 comprises the following steps:
(1) diblock or triblock polymer are dissolved with dichloromethane, make the solution that concentration is 5～100mg/ml;
(2) paclitaxel is dissolved in the above-mentioned polymer solution, making its concentration is 1～10mg/ml;
(3) above-mentioned organic solution is joined in the aqueous solution that contains stabilizing agent polyvinyl alcohol or gelatin, the volume ratio of organic solution and aqueous solution is 1: 20～1: 5, and the mass concentration of stabilizing agent in aqueous solution is 1～10%;
(4) with above-mentioned mixed liquor emulsifying, with 5～20 times of volumes of distilled water diluting that contain the stabilizing agent polyvinyl alcohol, the vacuum volatilization organic solvent is 1～2 hour then;
(5) adopt the high speed centrifugation separation method, 2000～20,000rpm collects Nano microsphere down, and the reuse distilled water wash is removed the residual stable agent, and lyophilization again obtains pressed powder.
5, the preparation method of the described Biodegradable high-molecular Nano microsphere of claim 4 is characterized in that using homogenizer emulsifying, mixing speed 6000～15,000rpm, 20～120 seconds time.
6, the preparation method of the described Biodegradable high-molecular Nano microsphere of claim 4 is characterized in that using the emulsifying of ultrasonic emulsification machine, ultrasonic power 20～200W, 30～120 seconds time.
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| CN106727617A (en) * | 2016-12-28 | 2017-05-31 | 四川省人民医院 | The nanometer formulation and preparation method of a kind of anticancer pharmaceutical composition and its application in malignant tumour is treated |
| CN107260683A (en) * | 2008-09-25 | 2017-10-20 | 新加坡纳诺泰克药物科技有限公司 | A kind of medicament nano particle delivery systems |
| CN108339152A (en) * | 2018-02-05 | 2018-07-31 | 北京化工大学 | It is a kind of with antibacterial-porous microsphere cytoskeleton and preparation method thereof for facilitating bone difunctional |
| CN109135015A (en) * | 2018-08-20 | 2019-01-04 | 蚌埠市维光塑胶制品有限公司 | A kind of Degradable environment-friendlyplastic plastic bag |
| CN114342930A (en) * | 2022-03-01 | 2022-04-15 | 中国农业科学院植物保护研究所 | Pesticide nanocapsule and preparation method thereof |
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2004
- 2004-03-19 CN CNA200410010733XA patent/CN1561987A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107260683A (en) * | 2008-09-25 | 2017-10-20 | 新加坡纳诺泰克药物科技有限公司 | A kind of medicament nano particle delivery systems |
| CN106727617A (en) * | 2016-12-28 | 2017-05-31 | 四川省人民医院 | The nanometer formulation and preparation method of a kind of anticancer pharmaceutical composition and its application in malignant tumour is treated |
| CN106727617B (en) * | 2016-12-28 | 2019-11-05 | 四川省人民医院 | The nanometer formulation and preparation method of a kind of anticancer pharmaceutical composition and its application in treatment malignant tumour |
| CN106620677A (en) * | 2017-02-06 | 2017-05-10 | 北京大学第医院 | Urokinase preparation based on polymer carriers and preparing method of urokinase preparation |
| CN106620677B (en) * | 2017-02-06 | 2020-05-08 | 北京大学第一医院 | Urokinase preparation based on high-molecular carrier and preparation method thereof |
| CN108339152A (en) * | 2018-02-05 | 2018-07-31 | 北京化工大学 | It is a kind of with antibacterial-porous microsphere cytoskeleton and preparation method thereof for facilitating bone difunctional |
| CN109135015A (en) * | 2018-08-20 | 2019-01-04 | 蚌埠市维光塑胶制品有限公司 | A kind of Degradable environment-friendlyplastic plastic bag |
| CN114342930A (en) * | 2022-03-01 | 2022-04-15 | 中国农业科学院植物保护研究所 | Pesticide nanocapsule and preparation method thereof |
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